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DEPARTMENT OF HEALTH AND HUMAN SERVICES
FOOD AND DRUG ADMINISTRATION
CENTER FOR DRUG EVALUATION AND RESEARCH
ADVISORY COMMITTEE FOR PHARMACEUTICAL SCIENCE
CLINICAL PHARMACOLOGY SUBCOMMITTEE
Wednesday, November 3, 2004
8:05 a.m.
Hilton Washington, D.C. North
620 Perry Parkway
Gaithersburg, Maryland
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C O N T E N T S
PAGE
Call to Order 3
Conflict of Interest Statement 5
Update on Previous Meeting Discussions/
Introduction to the Topics of This Meeting 7
Topic 1: Pharmacogenetics of Irinotecan
Introduction 30
Scientific and Clinical Evidence 49
Current and Future Perspectives on
Irinotecan Pharmacogenetics 76
Clinical Utilities of Genotyping 113
Committee Discussions and Recommendations 143
Open Hearing 166
Topic 2: Drug-Drug Interaction Concept
Paper: Issues Related to CYPs, Transporter-
and Induction-based Interactions and
Multiple Inhibitor Drug Interaction
Studies
Conflict of Interest Statement 206
Relevant Principles on Drug Interaction
Concept Paper 209
A Scientific Perspective 255
Induction-Based Interactions 269
Multiple Inhibitor Studies 323
Committee Discussions and Recommendations 345
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P R O C E E D I N G S
[8:05 a.m.]
DR. VENITZ: Okay; good morning, everyone.
Welcome to the Clinical Pharmacology Subcommittee
meeting. We have a full agenda for today, and
before we proceed with our agenda, I would like to
go around the table and for every person sitting on
this table to introduce him or herself, please.
Gerry, do you want to go ahead?
MR. MIGLIACCIO: Gerry Migliaccio,
vice-president, global quality operations, Pfizer.
DR. BLASCHKE: Terry Blaschke, Stanford
University.
DR. BARRETT: Jeff Barrett, Childrens
Hospital, Philadelphia.
DR. CAPPARELLI: Edmund Capparelli,
University of California, San Diego.
DR. DAVIDIAN: Marie Davidian, North
Carolina State University.
DR. DERENDORF: Hartmut Derendorf,
University of Florida.
DR. GIACOMINI: Kathy Giacomini,
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University of California, San Francisco.
DR. HALL: Steve Hall, Indiana University
School of Medicine.
DR. JUSKO: William Jusko, University at
Buffalo.
DR. VENITZ: Jurgen Venitz, Virginia
Commonwealth University.
MS. SCHAREN: Hilda Scharen, FDA Center
for Drugs, executive secretary.
DR. MCLEOD: Howard McLeod, Washington
University.
DR. SADEE: Wolfgang Sadee, Ohio State
University.
DR. WATKINS: Paul Watkins, University of
North Carolina.
DR. RAHMAN: Atiko Rahman, FDA.
DR. WILLIAMS: Grant Williams, oncology
drugs, FDA.
DR. PAZDUR: Richard Pazdur, oncology
drugs, FDA.
DR. LESKO: Larry Lesko, Office of
Clinical Pharmacology and Biopharmaceutics at FDA.
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DR. VENITZ: Thank you, everyone.
Our next step is to review the conflict of
interest statement, and Ms. Scharen is going to do
that for us.
MS. SCHAREN: Good morning. The following
announcement addresses the issue of conflict of
interest and is made a part of the record to
preclude even the appearance of such at this
meeting.
Based on the submitted agenda and all
financial interests reported by the subcommittee
participants, it has been determined that all
interest in firms regulated by the Center for Drug
Evaluation and Research present no potential for an
appearance of conflict of interest with the
following exceptions: in accordance with 18 USC
208(b)(3), the following participants have been
granted waivers: Dr. Paul Watkins has been granted
a waiver for consulting with the sponsor and a
competitor on unrelated matters. He has received
less than $10,001 per year from the sponsor and
between $10,000 to $50,000 per year from the
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competing firm.
Dr. Kathleen Giacomini has been granted a
waiver because her spouse is a member of the
speakers bureaus for the sponsor and a competitor.
He lectures on matters unrelated to the issues to
be discussed at this meeting. He receives less
than $10,001 per year from the sponsor and between
$10,001 and $50,000 per year from the competing
firm.
Dr. Edmund Capparelli has been granted a
waiver for unrelated consulting for the sponsor.
He receives less than $10,001 per year. A copy of
the waiver statements may be obtained by submitting
a written request to the agency's Freedom of
Information Office, Room 12-A-30 of the Parklawn
Building. In addition, Dr. William Jusko has been
recused from participating in this portion of the
meeting.
We would like to note that Dr. Paul
Fachler is participating in this meeting as
nonvoting industry representative acting on behalf
of regulated industry. Dr. Fachler's role in this
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meeting is to represent industry interests in
general and not any one particular company. Dr.
Fachler is employed by Teva Pharmaceuticals.
In the event that the discussions involve
any other products or firms not already on the
agenda for which an FDA participant has a financial
interest, the participants are aware of the need to
exclude themselves from such involvement, and their
exclusion will be noted for the record. With
respect to all other participants, we ask in the
interests of fairness that they address any current
or previous financial involvement with any firm
whose product they may wish to comment upon.
Thank you.
DR. VENITZ: Thank you, Hilda.
Our first agenda item is Dr. Lesko, who is
going to bring us up to date on the outcomes of our
previous meetings and who is going to set the stage
for the next day and a half.
Larry?
DR. LESKO: Thank you, Dr. Venitz and good
morning, everybody, and welcome to our fourth Clin
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Pharm Subcommittee meeting of the Advisory
Committee for Pharmaceutical Sciences. And I'd
like to say that we've been looking forward to
today's meeting, and I think we have three
interesting topics that we will be looking for your
input and discussion of as we move forward with
these particular areas.
Following the first couple of meetings,
there was some interest in sort of stepping back
and reflecting and recapping on some of the topics
that have been previously presented to the
subcommittee and in particular to reflect upon the
value of the meeting in terms of what FDA has
accomplished with the input from the committee.
And what I'm going to do now is summarize the
topics that we've discussed at prior meetings along
with some of the status of the projects that we've
brought before the Committee.
Let me first say that again, we have some
new members on the Committee, so this will be very
helpful, I think, for those individuals, but this
Committee was established in May of 2002, and in
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putting the Committee together, we selected
individuals with very specific expertise in broad
areas of clinical pharmacology that was
cross-applicable across many of the therapeutic
areas that clinical pharmacology deals with, and
those three areas were pharmacogenomics,
pharmacometrics and pediatrics, three broad areas,
but as we've seen with the past meetings, various
subtopics that are of interest to clinical
pharmacology. The three prior meetings occurred in
October 2002, April 2003 and last November.
I'll begin with some of the topics that we
covered during these meetings, and you'll see that
the topics were not confined to one or another of
the advisory committees. We've used our meetings
in a continuous fashion as the projects unfolded,
and the first topic that we actually brought before
the Committee was a methodology for identifying
patient subgroups at risk for toxicity. These are
the subgroups that represent specific or special
populations such as those with renal impairment.
And what we did in the early meeting was
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propose a quantitative method that was based upon a
number of features that we thought would be
beneficial, not only the mean exposure of the drug
in test populations such as the renal impaired
population and reference populations like the
healthy volunteers, but also, we proposed a method
that looked at the distribution of exposure values,
and then, from that distribution and comparing
those two distribution curves, identified a
critical cutoff value at the high end of the
distribution curve based on the exposure response
relationship.
What we are trying to get at here is a
cutoff value above which the risk of toxicity was
unacceptable from a clinical perspective. In
addition, we showed how we could calculate the
probably of a clinically significant response
beyond that cutoff, and we proposed a standardized
decision tree for dosing adjustments.
The summary points of our discussion was
that we linked population PK with clinical outcomes
through examples with unresolved questions. We
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discussed exposure response methodologies, using
modeling and simulations of adverse event
probabilities through drug-drug interactions. We
also discussed in some of our earlier meetings
decisional analysis based on exposure response
methods for assessing QT risk in special
populations.
These were intended to be examples of the
methodology, and inherent in those examples was
some methodological questions and issues that we
brought before the Committee for discussion.
So what did all of this lead to? Well,
the status of this project was that we've currently
implemented this methodology in our NDA reviews.
The methods we proposed to the Committee or a
variant of them as we went through the process are
routinely used in the quantitative analysis of
exposure response data for efficacy and safety.
The primary impact of the topic and the Committee's
recommendations have been for us in the office, we
use these methodologies and recommendations to
formulate our dosing adjustments that we recommend
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for inclusion in the package insert or in the
product label.
So we really went to several methods then
from our discussions here, selecting each of them
on a case-by-case basis, depending on the question
and the issues. That was the identification of
patient subgroups at risk.
We also brought another methodology that
was intended to do basically the same thing, and
that was the utility function for optimizing dosing
strategies. The summary points associated with
this topic was that we had proposed the utility
function as a methodology based on the probability
of either an adverse event or the absence of
toxicity taking into account the magnitude of harm
if the adverse or toxicity occurs.
We worked on this project for some period
of time, and the status at the moment is that we've
postponed further development, not that it wasn't a
worthwhile project, but the underlying approach was
difficult for us in implementation. Underneath
this approach was assigning relative weights to the
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value of the efficacy versus the value of the
toxicity, each of which can range from marginal to
significant, and thereby defining a therapeutic
index for the drug.
One of the ways you define these
endpoints, if you will, upper and lower limits of
acceptability and the relative benefit-risk is to
ask clinicians, which we did. We also searched
literature and looked for applications, and we
found that the approach for our purposes in
regulatory decision making was unsatisfactory
because of the difficulty in defining targets and
penalties for different measures of the utility
function.
That being said, the method certainly has
merit, and we have seen this in terms of drug
development. It certainly has merit in its
application to the selection of doses to be used in
clinical trials during the drug development
process, and we know of examples where this is, in
fact, done by sponsors. But for our purposes, at
this point in time, we have not been able to
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implement it as a regulatory, quantitative tool for
decision making.
The next topic that we had before the
Committee was using exposure response relationships
in the pediatric decision tree, which is an
appendix to our exposure-response guidance that was
released to the public in April of 2003. What we
had is summary points from these discussions, which
cover two of our meetings, was a proposal for the
design of a pediatric database to effectively
extract new knowledge from the in-house studies.
This was a data mining exercise, so that we could
use the information to update our pediatric
decision tree, which right now, is used
conventionally across our therapeutic areas.
We asked the Committee to comment and
recommend the highest priority questions or queries
from this database assuming that we could establish
it, and some of the things we presented to the
Committee using the database at the time was a
model for pediatric clearance in order to predict
it, which took into account age, adult PK and
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metabolism.
We subsequently proposed a systematic
pediatric research project that was fairly
ambitious. We wanted to evaluate the trends in
exposure response with age, using the information
that we had in house. We wanted to develop a
standardized approach for use across therapeutic
areas for population PK studies, and we wanted to
develop a computer-aided pediatric template for
study design that we can use during the IND process
in designing studies in collaboration with a
sponsor.
So the status of this project, following
our deliberations at the Committee, is that it's
ongoing. The progress on the database itself has
been limited for a variety of reasons. We had
difficulty accessing data in our files because of
the nonuniformity in the way data comes in. Some
of it is electronic; some of it is manual. It
became a laborious process to assemble this data,
and it's still in an ongoing mode.
The other issue that we found in mining
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our database was the availability of standard PK
and PD information. It was heterogeneous. We
could not easily take everything that we had
received in the files and assemble it into a
database that would be consistent across the
submissions. So it was a major work effort for us
to begin, but we have begun, although it's not a
complete project by any means.
We had proposed to the Committee a
pediatric research project, as I said, and this was
funded by CDER in June. I have June 2003. It
actually is 2004. Last couple of months, we
received money from the Center to fund this
project. It's being headed by Dr. Peter Lee, and
we've just begun to get going on the project.
We've hired four scientists under a contract.
We've established a steering committee for this
research. It has commenced, and we have some
12-month milestones.
So the input, the project are all ongoing,
and we're looking forward to sharing the results of
that project with the Committee as we move forward
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into next year.
The next topic that we covered in the
early meetings was the genetic polymorphism of
TMPT. The summary points from this discussion
included a presentation on the scientific and
clinical evidence that linked three different TMPT
genotypes with the incidence of myelosuppression.
What we discussed was a general framework for
consideration of analytical validation, clinical
validity and clinical utility for improving
benefit-risk and pharmacogenomics.
The third summary point was the discussion
that we had in front of this Committee related to
the revision of the label of 6-mercaptopurine that
would include dosing adjustments based on genotype
and the more rich information on what we know to be
the case with regard to polymorphism of TPMT.
The status of this project is that with
the input of this Committee and our Pediatric
Oncology Subcommittee, the project is in essence
complete. Both committees, if you recall some of
the discussion that we had at this Committee,
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recommend a revision of the label of 6-mp to
include TPMT information in various sections of the
label. Negotiations with the sponsor of these
products are basically complete, and the updated
label for both of the thiopurines will be available
in early 2005.
The next topic that was really a new topic
back in April of 2003 was our evaluation and
labelling of drug interactions of NMEs, an
important topic because we were just beginning the
initiation of the revision of our in vitro and in
vivo guidances for industry on drug interactions.
And a summary of what we presented at the Committee
was an in vitro drug interaction decision tree for
CYP enzymes and associated label language that
would go with that decision tree. We discussed
some of the scientific basis for policy decisions
related to NDA review, label language and class
distinctions for drug interactions, and we
discussed some specific drug-drug interaction
studies involving transporters, specifically PGP
and, by extension, some of the other transporters
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that are sort of on the front edge of the drug
interaction area.
The status of this topic is that it's
complete in many ways, although we have a little
bit more work to do, but the revision of the
guidance, which was the process that was behind the
topic we brought before the Committee is nearly
complete. The working group has been working on
this for some time, and we're getting close to
finalizing that guidance, which would be an update
of our current in vitro and in vivo drug
interaction guidances.
Furthermore, the topic that we've
discussed here has been included as a topic and
discussion point in the office's GRP drug-drug
interaction map and cross-labeling map, so again,
we try to transfer the knowledge and information
that we've learned through this Committee to
day-to-day practice in terms of IND and NDA
reviews.
A year ago, we introduced another new
topic. It was the end of phase 2-A meetings, and
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we had a very useful discussion on the topic. We
had as a background, if you remember, the concept
paper on the end of phase 2-A meeting, and what we
presented was the principles of the concept, and we
received again a significant input on the goals,
the process, the obstacles and the metrics of
success of the end of phase 2-A meeting.
With regard to the concept paper, we have
worked on the development of a guidance for
industry on the end of phase 2-A guidance. We
anticipate this guidance will be a final guidance,
in that it's not necessarily a controversial
guidance. We like to get it out fairly soon.
However, the status is ongoing, and over
the past year, we've had at least four significant
end of phase 2-A meetings. These had to do with
the questions that we had in the concept paper.
They involved a fair amount of modeling and
simulation. In one case, we have a disease state
model that came out of the meeting that was very
useful for simulating phase 2-B and 3 trials. And
by all indications, these meetings have been a
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success, both by comments we've received from the
sponsors and by comments we've received from the
medical divisions with whom we coordinate these
meetings.
So we're very optimistic about this
process as a so-called critical path activity that
has the potential to impact the efficiency, the
informational content of the drug development
process.
As I say, the deliberations were very
helpful to us in writing a draft guidance for
industry on the end of phase 2-A meeting. It's
undergone internal review, and for all practical
purposes, it's complete. There is a process to
release a guidance, and that would probably take us
through the first quarter of 2005, when we make
that guidance public.
Another topic we discussed before the
Committee was the quantitative analysis of QT. The
summary points that we presented to the Committee
was some approaches using modeling and simulation
and also metrics for assessing QTC interval
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prolongation. If you recall, the metrics that we
talked about were pros and cons of maximal change
from baseline area under the QTC time curve, et
cetera. And we asked for input from the Committee
on these methodologies that we could begin to apply
in the review of QT studies within the NDA
database.
Status of this is still ongoing. There's
a lot of current discussion on standardization of
both study design and data analysis of these kinds
of studies. We've made recommendations and
presentations that have stemmed from our discussion
here at the Advisory Committee to the CDER QT
working group, who was favorably impressed by what
we delivered in terms of a quantitative approach to
assessing the risk of QT.
We also discussed drug interactions
involving somewhat unrecognized and
underappreciated potential drug interactions
involving CYP2B6 and 2C8. The summary of our
presentation and discussion here at the Committee
was that we sort of took an inventory of our
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current understanding of inhibition reactions in
particular that are based mechanistically on the
2C8 and 2B6 pathways.
We discussed some of the reliability of
the in vitro and vivo associations of these drug
interactions, similar to what we do for the more
common CYP enzymes to see to what degree these in
vitro studies can be a guide to the need to do
clinical studies, and if we do clinical studies,
what are the model drugs? So we did present some
examples to the Committee with model drugs, and
I've listed a few of them there asking for comment
on the methodology and the use of the information.
So the status of this project is ongoing.
The input was seriously considered in the context
of our CDER working group on drug-drug
interactions, and there's probably a good chance
we'll be discussing more of this in subsequent
Committee meetings.
So anyway, that in a nutshell is what
we've brought before the Committee as topics. I
think you can see how they fit into those three
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broad areas of pharmacogenetics, pharmacometrics
and pediatrics. We've branched out into the
drug-drug interaction area as the need arose for us
to bring this to a public discussion.
So my reflections on the first three
meetings as we move into our next one is that the
topics we've brought before you as an advisory
committee have been challenging. We recognize they
have been diverse. They've been as diverse as the
expertise of the membership.
Just so you appreciate how we bring topics
to the Committee, we try to select topics that are
relatively new and important to NDA reviews such as
the quantitative methods. You've noticed that they
are not usually drug-specific, because we bring
general topics that are cross-applicable across
many therapeutic areas. We've brought topics to
the Committee that I think are cutting-edge
science, the drug interaction area in particular
with transporters and some of the new CYP enzymes
are areas that we have a lot of issues to resolve
in terms of what we would recommend to drug
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sponsors and their drug development programs.
And finally, some of the topics we've
brought here had an element of controversy, because
they were new, and I would say in our
pharmacogenetic area, we've had a lot of good
discussion and clarity about the integration of
pharmacogenetics into product labels and into the
assessment of benefit risks.
So in short, a compliment to the
Committee. The value of this Committee has been
tremendous. I think it's the only committee that
has dealt with those topics. It has given us
significant guidance on decisions we have to make
in terms of the specific areas that we've brought
forward, and it has had a very significant
influence on our clinical pharmacology program at
FDA.
And finally, many committees do vote.
Usually, this is characteristic of committees in
which specific drugs are brought forward for voting
on one issue or another associated with that. We
haven't done that very much in this Committee. The
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nature of our topics really haven't lent themselves
to voting, because they are more general. We
anticipate we will be doing more of that, including
some of the topics that we will bring before you
today, but the primary benefit is not the voting,
necessarily; the primary benefit that we've
received is the copious notes that we've been able
to take and the benefit that we've had from the
discussion of the Committee.
So for all of this, I would thank you for
your service to the FDA and service to the public
as members of this Committee and, frankly, look
forward to further very interesting discussions
with you all.
I will pause at this point, and it looks
like if there's any questions, I'd be happy to
answer those. I'll turn it back to the Chair
before I move on to a specific topic.
DR. VENITZ: Thank you, Larry.
Any comments or questions by Committee
members?
I'm interested in the end of phase 2
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status. What are the metrics of success that
you're considering right now to evaluate whether
this program is going to be a success?
DR. LESKO: Yes, the metrics of success
really have been a questionnaire that we're
preparing to send to the company. We also call the
company to try to get feedback on what we did as a
process and what recommendations we gave them in
terms of value. We interact both with the clinical
group at sponsors. We work with the
biostatisticians and the clin pharm folks as well
as the regulatory folks at the various companies.
We also survey the medical division that
we coordinate the meeting with to see if what we
brought to the table in terms of the quantitative
methods was perceived to have value, and then,
finally, we have, in one form or another, a
debriefing of the internal team that worked on that
preparation for the end of phase 2-A meeting to get
back into lessons learned and see what we can do
better.
What has it all meant? I think we need to
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have more experience with it, but as I said in my
remarks, I think the feedback we've gotten both
from the company and the internal participants has
been very encouraging for us to go forward. These
have not been small efforts. We're somewhat
overwhelmed by the effort that goes into preparing
for these meetings in the short time frame that we
have, and it is very resource-intensive, so it's
important to us to actually get good metrics of
success, and we're going to be collecting those,
and I'd like to share that, maybe, with the
Committee at some point in time.
DR. VENITZ: And I was exactly going to
encourage you to do that, because as you remember,
the discussion that we had, even though the
Committee was very much in favor of this
initiative, there was concern about resource
allocation and so on, so you really have to
demonstrate that there is a value in doing this.
DR. LESKO: Exactly, and I remember those
comments exactly. And there was no rebuttal to
those. We just had to get into it and try it, and
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indeed, we have gotten into it and tried it. But,
you know, aside from what the impact was on drug
development, the impact on us in FDA being able to
work together in a quantitative way to discuss drug
development and benefit risk in a way that you can
put on the table in terms of a model and do a lot
of what-if scenarios has really been good for us,
and I think it's, again, made us a stronger group
within the agency aside from whatever impact it had
on drug development.
It's oftentimes spoken about in the
context of critical path now, which came out this
past March of one of the leading initiatives of the
critical path project that has the potential to
influence in a positive way the drug development
process so--
DR. VENITZ: Thank you. Any other
comments, questions?
[No response.]
DR. VENITIZE: Then why don't you proceed
with the topics for the next day and a half?
DR. LESKO: Okay; so, now, switching to
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the topics for the next day and a half, we're
bringing three projects, topics, to the Committee.
The first of those this morning is going to be in
the area of pharmacogenetics. Specifically, we're
going to be discussing the scientific and clinical
evidence that surrounds the UGT1A1 polymorphism and
its relationship to the pharmacogenetics of
Irinotecan.
This afternoon, we're going to bring to
the Committee a topic in the area of drug-drug
interactions. We'll be talking about metabolism
and transporter-based interactions, and again, this
is a relative topic to the revised guidance for
industry on the on-drug interactions. And thirdly,
we're going to bring to the Committee a topic from
the world of pharmacometrics, but it also is from
the world of the critical path.
We're beginning to focus on specific
critical path activities that we would like to
advance, and tomorrow, we'll be talking about one
that deals with the greater use of biomarkers
within the context of drug development and their
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systematic progression to potential surrogate
markers. We'll primarily be talking about the
project and the project plans in the latter area
but not necessarily on any specific biomarker in
any given therapeutic area but a more general plan
that we hope to get input on as we move forward
with it.
So those are the three topics, and I think
what I'll do now is really launch into the first
topic, but I want to pull up the slides for that.
So the first topic of the morning is the
pharmacogenetics of Irinotecan. And we'll be
talking about the scientific and clinical impact of
UGT polymorphism. And my role up here right now is
to present a background to the topic and then turn
it over to the individual presenters that we've
scheduled for the morning prior to the discussion
with the Committee.
I'll start out with the labeling
regulations that apply to both new and to
previously-approved drugs, and the labeling
regulations are that if evidence is available to
32
support the safety and effectiveness of the drug
only in selected subgroups of the larger population
with the disease, the labeling shall describe the
evidence and identify specific tests needed for
selection and monitoring of patients who need the
drug. Obviously, this is not pharmacogenetic
specific but certainly I think encompasses
pharmacogenetic testing and information.
Pharmacogenetic information on drug labels
in general is not anything new. There's no current
barriers to including this information in product
labels. Many of you, I'm sure, are familiar with
examples of Herceptin, which is probably one of the
most well-known examples of pharmacogenetic
information on product labels. That is one example
of where a test and a drug therapy are used in
conjunction with one another.
If one were to survey the PDR and look at
package inserts over the years, about 35 percent of
the approved drugs have pharmacogenetic information
in the label. That doesn't necessarily mean that
that information is clinically important or
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clinically relevant. Much of it is descriptive,
and much of it doesn't really translate into what
physicians would do in clinical practice having
that information in hand.
On the other hand, this is reflecting many
years of pharmacogenetics in terms of the
well-known biomarkers of cytochrome enzymes, and
it's only now that I think we're beginning to see
evidence that some of these enzymes are clinically
important and ought to be considered more seriously
in dosing of approved drugs.
A couple of other examples: Thioridazine
is a previously-approved drug, and if you look at
the package insert for that, there's a black box
warning in there that warns physicians and patients
that they ought to avoid this drug in 2D6 poor
metabolizers because of the toxicity risk
associated with poor metabolism, and Thioridazine,
of course, is a 2D6 substrate.
Atomoxetine is an example of a relatively
new drug for attention deficit disorder. There was
information from the clinical development plan
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about the relationship between pharmacogenetics,
specifically poor metabolizers and extensive
metabolizers and clinical outcomes in terms of
efficacy and safety. This was information that
both the sponsor and the agency agreed is
worthwhile to put in the label, and in fact, we
included it in the label in seven different
sections, ranging from the laboratory test section
to the clinical pharmacology section. However,
there was no reason to require or suggest that a
test would have to be done prior to using the drug.
Cetuximab is a drug that was approved that
includes genomic information and particularly tumor
genomics about receptor positivity. This drug is
an EGFR inhibitor, and there's some general in
there about the relationship between the drug and
its pharmacology and its receptor positivity from a
mechanism standpoint. Again, there was no
recommendation to require a test prior to
prescribing the drug.
Finally, as I mentioned in my opening
remarks, we have discussed before the Committee
35
6-mercaptopurine and azathioprine, and these
labels, for all intents and purposes have been
updated to include the polymorphism information in
multiple sections. That was deemed important.
With regard to the outcome of the 6MP and
TMPT polymorphism, in many ways, it was a step in a
general framework for assessing the
pharmacogenetics of approved drugs. We are trying
to create a structure for that type of discussion
as we look at approved drugs that may benefit in
terms of the inclusion of pharmacogenomic
information, so we start out in this case with the
absence of information in the label, which was then
discussed at the Clin Pharm Subcommittee as well as
the Pediatric Oncology Subcommittee.
The new labeling, as I said, has been
revised in consultation with FDA and includes, now,
data on increased risk of severe myelosuppression
associated with genotypes of TMPT. So we think the
label has been updated with useful information for
clinicians and patients as they weigh their options
of using TMPT testing to guide along with other
36
adjunctive tools and clinical information to guide
the treatment of 6MP.
The general process that we've tried to
create as a general framework for assessing
pharmacogenetics, particularly of
previously-approved drugs, where we don't have the
benefit of new drug development plans and
prospective trials, is to think about the general
process of approaching the assessment of
pharmacogenetics and its value in inclusion on
label.
In this meeting, we wouldn't mind having
comments on this. It's not one of the specific
questions, but I think we need to think about a
general process where we develop the appropriate
questions. What is the question we're asking of a
pharmacogenetic test or a piece of information? We
try to capture the relevant evidence. Oftentimes,
that comes from the published literature. You'll
see today how we try to abstract and summarize in a
sort of meta-analysis the scientific and clinical
evidence that allows us to go forward and make a
37
decision.
We think it's important to evaluate the
quality of the studies, and that's what we've done
in this case of 6MP as well as the Irinotecan we'll
talk about. We look at the overall strength of the
evidence from the individual studies, and we
consider other factors in the relabeling decision
that has to do with test availability, test
performance and things of that sort, and then,
finally, we move to the specific language for the
label.
So it's a general framework that we walk
through as we think about this drug or that drug or
the next drug where pharmacogenetic information may
possibly be pertinent to the improvement of
benefit-risk or dosing.
Now, today, you're going to hear about the
current understanding of pharmacogenetics and
neutropenia with regard to Irinotecan. What I've
summarized in this table is on the left-hand side,
groups that begin with all of the patients and then
moving over from left to right the prevalence of
38
genotypes and the risk of toxicity that we
currently feel is the case. And this comes from
the data of one paper that's been published by
Innocenti in 2004, and what this shows basically is
that all patients have a relative risk of 10
percent of developing grade three/grade four
neutropenia.
Breaking down the general population, we
have a subgroup that represents the 7/7 genotype
for UGT. Prevalence of that genotype is
approximately 10 percent. The relative risk of
toxicity, that is to say, the penetrance of
toxicity is 50 percent. Patients that are
heterozygous, prevalence of 40 percent with a
relative risk of toxicity of 12.5 percent, and at
least in this study, patients that were 6-6 had a
prevalence of 50 percent and a relative risk of
toxicity of zero percent.
So you see more of that data, but this is
the compelling data I think that facilitated
bringing this before the Committee. So we see the
potential for a test for UGT testing in this figure
39
that oftentimes is used to represent the value of
pharmacogenetics. And basically, we're looking at
patients with the same diagnoses that require this
drug for its approved indication and an overall
risk of 10 percent for neutropenia.
We know, however, in this general
population is a mixture of people with different
genotypes, and the value of the tests and the way
we'd like to consider this is what would this test
bring to the table as an adjunct piece of
information to use this drug in the most optimal
way? We have on the top the profile for the high
risk patient that we could identify with a genomic
test. Not all of those patients identified, as
you'll see, will develop frame toxicity. We have a
middle group that represents those at moderate
risk, and we have the bottom group based on the
data I've showed you that has a relatively low
risk.
So I think the goal of pharmacogenetics in
general and in this case specifically is to try to
differentiate and discern the differences between
40
patients who otherwise would be perceived to be
those patients with the same disease and the same
indication for the drug and bring that
differentiation as a tool to the clinical practice
for improving benefit-risk and drug and dose
selection.
So that's the context for what we want to
do this morning. So we'll begin with a discussion
of the scientific and clinical evidence that links
the UGT polymorphism with severe neutropenia.
We'll discuss, then, the role that testing can play
in identifying patients predisposed to severe
toxicity.
Now, I want to share with you that we have
had very positive interactions with the sponsor on
this topic. The sponsor is committed to providing
informative and understandable labeling as is the
FDA for all its drug products. Both agree that
information on UGT polymorphism and the risk of
toxicity on the label is of great importance. Both
sponsor and FDA agree to update the label to fully
inform prescribers and patients about
41
pharmacogenetics.
However, in this discussion today, we're
not going to get into what the label will say or
what the specific wording will say. We'll be
talking primarily about the scientific and clinical
evidence and the strength of evidence and the
questions that we've brought before the Committee.
I'll say this once now, just to sort of
create a framework for what you're going to hear.
We'll go back to the questions, obviously, near the
end of the morning. But basically, we're going to
ask is the clinical and scientific evidence that
you'll hear sufficient to demonstrate that
homozygous genotypes, the 7/7 genotypes, are at
significantly greater risks for developing
neutropenia and/or acute and delayed diarrhea from
therapy.
We're going to ask based upon what is
known on this relationship between Irinotecan
containing regimens and toxicity three
subquestions: do we know enough to recommend the
starting dose of the drug in the single agent and
42
combination therapy? What would be the risks and
benefits of the recommended starting dose? And if
we need more information, what is the appropriate
study to evaluate dosing in these types of
patients?
We'll ask how information about genotype
can be used in combination with bilirubin. This
is, like a lot of genetic tests, not the end all
and be all, but it's an adjunct piece of
information that, used in conjunction with other
indicators like bilirubin, can be used to improve
clinical decision making.
And finally, you'll see some information
where we're going to ask is the measurement of the
genotype sufficiently robust in terms of its
clinical sensitivity and specificity to be used as
a response predictor test for Irinotecan dosing?
So those are the questions and my
introduction. I could pause and turn it over to
the chair, or we can launch into the next
presentation.
DR. VENITZ: Any quick questions or
43
comments by the Committee before we start off on
the first topic?
DR. SINGPURWALLA: I hesitate to raise
these questions because I'm new here to this
Committee, but I'd like to draw your attention--I'd
like to go to that particular chart, where you had
prevalence and risk of toxicity. If I were to
understand correctly, the purpose of this chart is
to show that patients who are 7/7, and I don't know
what that means, have a 50 percent risk of
toxicity.
DR. LESKO: That is correct.
DR. SINGPURWALLA: There are two concerns
I have. One is why is the 10 percent prevalence
important? Because if you know the patient is 7/7,
then, the risk of toxicity is 50 percent. So the
fact that there are only 10 percent of individuals
who are of that particular category is not
relevant, unless you are giving the drug blindly,
without taking into consideration the
characteristics of them. So that's the first
question I want to ask.
44
DR. LESKO: Okay.
DR. SINGPURWALLA: Then, I have a comment
to make, and I'm not sure if this is appropriate,
but there's something called Simpson's Paradox that
arises in these particular contexts. And I'm
wondering if that has been taken into account.
DR. LESKO: Well, let's go to the first
question. I think in the first question, what I've
showed is that in the overall population, and you
use that term blinded. If you're blinded, and we
were all sitting around the room as potential
patients, the overall risk of toxicity is 10
percent. The question is which of the one out of
10 people are going to be most at risk for that
toxicity?
Without a test, you wouldn't know that.
You could obviously use other information that's
available on the drug and currently is in the label
regarding age or bilirubin levels. What the
genomic tests would do is to begin to differentiate
those people in the room, those 10 people around
the table that would be more at risk than the 10
45
percent risk for the general population, because
you're teasing out, obviously, the people that
would have a very low risk or no risk at all and
identifying those with a higher risk.
So if we took the general population,
subdivided it by genotype, then, the overall risk
would be 10 percent. It's only a reference mark.
I didn't mean to say more about it than that.
However, in this group of patients identified by a
genotype, by a test, the risk is much higher. It's
about 50 percent.
And what you'll hear in some of the
presentations is the likelihood ratio and relative
risk of developing this adverse event in that
defined subset by the genomic test, so that's the
relevance of the test and comparing it to the
current situation without and the future situation
with a test.
DR. SINGPURWALLA: Yes, but I'm still not
clear. If there is a 7/7 patient, I'm sorry; you
wouldn't blindly give the drug to anybody, any
person who shows up at random. You'd find out if
46
that is a 7/7 and then act accordingly; isn't that
correct?
DR. LESKO: Well, clinically, I'd think
you'd want to do that, because that would have a
role in making your decision to give the drug, what
dose to give and to consider other choices, but you
need something to identify that patient, and
currently, that information is not contained in the
package insert to guide the physician to make that
decision.
DR. SINGPURWALLA: I see. So now, given
that that is the case, then, I would strongly
encourage you to look at this notion, this concept
of Simpson's Paradox before you arrive at a 10
percent risk for patients overall.
DR. LESKO: Can you tell me what Simpson's
Paradox is?
[Laughter.]
DR. SINGPURWALLA: Well, yes, what is good
for--a drug is good for men, and a drug is good for
women, but a drug is not good for the population as
a whole. That's the paradox. Okay; some of your
47
statisticians will help you with that.
DR. LESKO: Okay.
DR. SINGPURWALLA: If not, I'll charge you
a fantastic consulting fee and help you.
DR. LESKO: Sounds good. I don't know if
you'd be on our advisory committee.
[Laughter.]
DR. SADEE: Larry, I have a comment, maybe
a different type of question that's brought up by
this polymorphism for Irinotecan.
The optimal dose, unquote, optimal dose
has been derived before these considerations, and
that includes a patient population that's really
inappropriate to calculate the optimal dose. So
what would be the position of the FDA to--in new
trials, where you combine Irinotecan? Do you go by
the old optimal dose, unquote, that included a
patient population that really shouldn't have been
included?
So the question would be how do we define
optimal dose in future trials to the normal
population, which is the inverse of saying what is
48
the optimal dose for those people who are at high
risk?
DR. LESKO: Right; yes, I don't think we
have the data to make that call. We'd like to know
the answer to that question, but I don't think we
have enough information to say what the optimal
dose would be for these subtypes. I'm not sure we
have enough information to talk about the optimal
dose for any of the patient groups.
However, we're going to discuss that as we
get further into the morning. In fact, I think
that's one of the questions we'll talk about: in
the absence of credible information to discern the
dose, what type of study and what type of study
design would be appropriate? And I think you'll
hear about some of the ongoing studies that will be
along those lines. So maybe we can leave that as a
partial answer and wait for the rest of the
presentations.
DR. VENITZ: Thank you, Dr. Lesko.
Then, our first speaker on that topic is
Dr. Atik Rahman. He's going to review for us the
49
clinical evidence of the role of UGT1A1 in
Irinotecan.
DR. RAHMAN: Good morning. I am Atik
Rahman, the acting deputy director of the Division
of Pharmaceutical Evaluation I, the Office of
Clinical Pharmacology and Biopharmaceutics. I'm
also the chair of the OCPB Pharmacogenetic Working
Group.
This morning, you have already heard from
Dr. Lesko regarding the approach that we took with
6MP and thiopurine methyltransferase enzyme. The
pharmacogenetics of thiopurine methyltransferase,
TMPT enzyme, and 6MP toxicity was discussed by the
Advisory Committee of the Pharmaceutical Sciences
in November of 2001. Subsequently, the topic was
also discussed by this Committee on April 23 and
also by the Oncology Drug Advisory Committee,
Pediatric Subcommittee on July 15 of 2003.
I will briefly discuss or update the
Committee on 6MP label modifications that resulted
from the Committee's deliberations and the FDA
interaction with the manufacturer of Purenithol. I
50
will follow that with the scientific and the
clinical evidence from the literature that we have
in the agency to demonstrate a relationship between
UGT1A enzyme polymorphism and its association with
Irinotecan toxicity.
6MP is inactivated by TPMT. TPMT is a
polymorphic enzyme. Ninety percent of the
caucasian and African-American population have
normal gene and normal enzyme activity. Ten
percent of the population have intermediate enzyme
activity, resulting from one deficient TPMT allele,
and one in 300 has low or no TPMT activity because
of two deficient allele in their gene.
There is a strong correlation between
genotype and phenotype, which is expressed as
either TPMT enzyme activity or as the levels of
6-thioguanine nucleotides in red blood cells.
A clinical study showed that 100 percent
of the homozygous patients required 6MP dose
reduction to prevent toxicity, compared to 35
percent of heterozygous and 7 percent wild type
patients. Currently, prospective trials are
51
ongoing to evaluate appropriate dose of 6MP in
acute lymphoblastic leukemia patients.
6MP is given with other myelosuppressive
therapy in the treatment of acute lymphoblastic
leukemia or ALL. Literature information indicated
a potential benefit of reducing the dose of 6MP in
patients with low to intermediate TPMT enzyme
activity. This reduction of approximately 50
percent 6MP dose in heterozygous and approximately
80 percent 6MP dose reduction in homozygous
patients allowed other myelosuppressive agents to
be given in full dose with 6MP during the entire
course of therapy.
Most of ALL protocol now avoid radiation
with 6MP because of the higher incidences of brain
tumors observed in TPMT-deficient patients in
previous trials.
Based on the advice of the advisory
committees and the manufacturer of Purinethol, Tiva
collaborated to include the information on TPMT
polymorphism and its relationship with 6MP toxicity
in the package insert of Purinethol. A new
52
subsection is included in the clinical pharmacology
section to describe the metabolism of 6MP and TPMT
polymorphism.
In the warning section, bone marrow
toxicity subsection includes a warning for
substantial dose reduction for homozygous TPMT
deficient patients. Information on the
availability of genetic tests is indicated in the
precaution section.
The availability of the test is mentioned
in the dosage and administration section of the
label, and substantial dose reduction is indicated
for patients with TPMT deficiency. In the future,
we hope to provide specific dosing recommendations
for both the homozygous and the heterozygous TPMT
deficient patients for 6MP therapy.
Now, I al provide you with the scientific
and clinical evidence that relates Irinotecan
pharmacogenetics with toxicity. Irinotecan is
indicated as a first line therapy in combination
with 5-fluorouracil and leucovorin for colorectal
cancer patients. The drug is also indicated as a
53
single agent for patients with metastatic
colorectal carcinoma, whose disease has recurred or
progressed after initial 5-fluorouracil-based
therapy.
Two phased randomized controlled
multinational clinical trials show that Irinotecan
in combination with 5-fluorouracil and leucovorin
increased the survival in first line colorectal
cancer patients compared to Irinotecan alone or
5-fluorouracil alone. Two multicenter randomized
clinical trials show significant increase in
survival for colorectal cancer patients whose
disease has recurred or progressed after prior
5-fluorouracil therapy.
Irinotecan is metabolized by
carboxyesterases to SN38, a metabolite which is
1,000 times more potent than the parent drug. SN38
is glucuronidated in the liver by UDP glucuronol
transferase family of enzymes, predominantly by
UGT1A1, and eliminated via biliary route.
Deficiency of UGT1A1 results in increased SN38
levels in plasma and in bone marrow cells, causing
54
hematologic and nonhematologic toxicities. These
toxicities result in dose delay, dose reduction and
hospitalization and even sometimes in deaths.
UGT1 gene is located on chromosome 2 and
contains at least 13 different promoter axons which
are spliced to common axons 2 through 5. UGT1A1 is
an isoform that is associated with bilirubin
glucuronidation. The isoenzyme has more than 30
variant alleles. UGT1A1*28 is a variant allele
that contains seven TA repeats in that TATA box of
the promoter region instead of six TA repeats.
Today, we will focus on UGT1A1*28 variant
only, because the agency believes that we have the
most mature data on this variant's association with
Irinotecan toxicity. I will use the term 7/7
genotype to refer to UGT1A1*28 variant in my
presentation.
Fischer et al studied the relationship
between UGT1A1*28 genotype and estradiol
glucuronidation mediated by UGT1A1 enzyme. Liver,
kidney, lung and intestinal tissues were tested for
UGT1A1, 1A6 and 2B7 isoenzymes. In the 7/7
55
genotype liver samples, the apparent Micholas
Mentin constant KM was not altered, but the V-max
was altered, compared to 6/6 wild type liver
samples. Liver samples with 7/7 genotype had a
fourfold lower activity of the enzyme compared to
the samples with normal gene expressions, as shown
in this bar plot.
As you have already heard, that in the
caucasian population, the frequency of homozygous
deficient 7/7 genotype is approximately 10 percent,
with a range from 5 to 15 percent. The
heterozygous 6/7 genotype is approximately 40
percent.
This slide illustrates the relationship
between the risk of severe neutropenia and diarrhea
and SN38 exposure. These data are from the phase
2-3 studies of Irinotecan in which weekly doses of
100 to 150 milligrams per meter square were
administered to patients with colorectal cancer.
In absence of individual PK data in these studies,
mean AUC data from earlier studies were used.
Despite the limited data, logistic regression
56
analysis suggested that the risk of severe
neutropenia and diarrhea increases with SN38
exposure.
The first article that I'd like to present
today is a clinical study that was conducted at the
University of Chicago by Dr. Mark Ratain and his
group. The article was published in the Journal of
Clinical Oncology this year. This was a
prospective study in 66 solid tumor or lymphoma
patients. The study evaluated the association
between the prevalence of severe toxicity and
UGT1A1 genetic variation.
The patients received 350 milligram per
meter square dose of Irinotecan every three weeks.
This is an approved dosing regimen for single agent
Irinotecan therapy. Toxicity was assessed during
cycle 1. Fischer's exact test was used to relate
genotype with pharmacokinetic parameters,
pretreatment bilirubin and absolute neutrophil
count.
I'd like to mention some of the highlights
of this study. The study has certain unique
57
features compared to the other studies that I'm
going to present subsequently. This is a
prospective trial with an adequate number of
patients who had 7/7 genotype. The study is clean
in terms of not having any contribution in toxicity
from other agents. Sometimes, it's hard to pin
down the culprit for toxicity in combination
regimen chemotherapy trials.
The onset of toxicity was rapid with the
first cycle of therapy. The PK assessment was
reliable, being conducted in a lab that has
pioneered an assay for this complex and unstable
molecule.
There was a significant difference in the
dose normalized AUC exposure between 7/7 genotype
and 6/6 genotype patients. A significant
difference was also noted between 6/7 and 6/6
genotype patients. This is a combined data set,
including 66 patients from the Innocenti study and
20 patients from another phase one study conducted
in the same institute, using 300 milligram per
meter square dose of Irinotecan.
58
This slide shows the relationship between
the maximal decrease in absolute neutrophil count
ANC as a function of SN38 exposure. Patients with
6/6 genotype are shown in blue. Those with 6/7
genotype are shown in green. And patients with the
7/7 genotype are shown in red. The square symbols
are the mean ANC nadirs and SN38 AUCs for the three
subgroups. The data were log-transformed and fit
using linear regression models. The blue line
shows the predicted curve for 6/6 and 6/7 genotypic
groups, and the red line shows the predicted curve
for the 7/7 patients.
The 7/7 genotype has a greater effect on
the ANC nadir versus SN38 AUC relationship compared
to the 6/6 and 6/7 genotypes. For the same AUC,
the 7/7 genotypes show a lower ANC nadir.
Overall, the study showed 50 percent of
the 7/7 genotype patients had grade four
neutropenia compared to 12.5 percent heterozygous
patients, and no wild type patients had grade four
neutropenia. There is a significant difference in
the exposure to SN38 between the
59
homozygous-deficient 7/7 patients and the 6/6
genotype patients as shown in the previous slide.
Also, the pretreatment bilirubin levels between the
7/7 and the combined 6/7 and 6/6 genotype patients
was significant.
The prevalence of grade four neutropenia
and grade three diarrhea in the overall
population--sorry, the prevalence of grade four
neutropenia was 9.5 percent, and the grade four--or
the severe diarrhea was 5 percent in this study.
Notable in this study, one patient died of
neutropenia-related sepsis who had 7/7 genotype and
had the highest total bilirubin level.
In the study, the grade four neutropenia
was significantly higher in 7/7 patients compared
with 6/7 and 6/6 patients. The relative risk for
grade four neutropenia for 7/7 patients was 9.3.
Only three patients in this study had grade three
diarrhea. One was a 7/7 patient, and the two
others were patients with 6/7 genotype. None of
the patients with 6/6 genotype had severe diarrhea.
The study conclusively established an association
60
between genotype and neutropenia.
This is a prospective phase two study
designed to evaluate the influence of UGT1A1
polymorphism on the toxicity profile, on the
response rate and on the overall survival in 95
colorectal cancer patients treated with four
Irinotecan containing regimens. Irinotecan
regimens were 350 milligram per meter square every
three weeks; 80 milligram per meter square weekly;
or 180 milligram per meter square biweekly.
Toxicity was evaluated during the entire duration
of treatment. No PK samples were collected.
Various statistical tests were applied to assess
the differences between the categorical variables
and between the related or unrelated continuous
variables.
Logistic regression was used as a
multivariate method to assess of genotype
independently predicted toxicities. I will not
present any efficacy data from this trial.
Neutropenia and diarrhea in this table
includes both grade three and grade four
61
toxicities. Forty percent, four out of 10 7/7
genotype patients had grade three/four neutropenia
compared to 15 percent patients with normal
alleles. Seventy percent of the patients with 7/7
genotype had severe diarrhea compared to 17 percent
patients with normal alleles. The cumulative dose
of Irinotecan received by 7/7 genotype patients was
1,398 milligrams per meter square, compared with
1,725 milligrams per meter square received by
patients with 6/6 allele.
The prevalence of grade 3/4 neutropenia
and diarrhea in the overall population was 21
percent and 31 percent respectively. Notable is
the incidence of diarrhea, which was higher in this
trial compared to what we have seen with other
Irinotecan-based trials.
Both univariate and multivariate analysis
showed statistically significant association
between appearance of diarrhea and 7/7 genotype
compared with 6/6 genotype. Hematologic toxicities
increased from 6/6 patients to 7/7 homozygous
patients from 15 to 40 percent but didn't achieve
62
statistical significance. Cumulative dose of
Irinotecan received by 7/7 patients were lower than
the dose received by 6/6 patients because of the
dose reduction that was necessary for the
appearance of severe diarrhea. This study
demonstrated a significant relationship between
genotype and severe diarrhea. The statement by the
author of this article shows a need for
genetic-based chemotherapy treatments for cancer
patients.
This is the third study that I'm going to
talk in detail about. This is a retrospective
study of 75 metastatic colorectal cancer patients
receiving two common Irinotecan containing
combination regimens. Irifufol regimen contains 85
milligram per meter square weekly Irinotecan, given
with 1,200 milligram per meter square weekly
infusional 5-fluorouracil plus 100 milligram per
meter square bolus leucovorin. Folfiri regimen
contained 180 milligram per meter square biweekly
Irinotecan given with 2,500 milligram per meter
square infusion of 5-fluorouracil and 400 milligram
63
per meter square leucovorin. No PK samples were
collected in the study. Kruskal-Wallis test was
used to assess the statistical difference among the
three populations.
Seventy-one percent of the 7/7 patients,
five out of seven, compared with 10 percent 6/6
patients, three out of 31, had grade 3/4
neutropenia. Sixty percent of the 7/7 patients had
neutropenic fever compared to no 6/6 patients
suffering from neutropenic fever. Neutropenic
fever was associated only with patients who carried
at least one deficient allele of UGT1A1.
Irinotecan courses had to be delayed in
five out of seven patients in the 7/7 group
compared with 21 out of 35 in 6/7 and 10 out of 31
in 6/6 group. 100 percent of the 7/7 patients
whose therapy had to be delayed for toxicity had to
be hospitalized compared with no 6/6 patients with
delayed therapy requiring hospitalization.
The prevalence of grade 3/4 neutropenia
and diarrhea in the overall population was 30
percent and 7 percent respectively. There was no
64
association between genotype and diarrhea because
of the low frequency of diarrhea in this trial.
There was a strong correlation between genotype and
grade 3/4 neutropenia. 100 percent of the 7/7
patients who had severe neutropenia needed delayed
therapy and hospitalization compared to none of the
6/6 patients who had neutropenia and/or diarrhea.
The authors mentioned in this article that
hematologic and digestive toxic events were not due
to 5-fluorouracil because all of the patients had
5-fluorouracil dose adjusted individually to avoid
severe 5-fluorouracil toxicity.
Literature includes other adequately-sized
studies that I'd like to summarize for the
Committee. These are the two PK studies that
evaluated the effect of variant alleles on
Irinotecan disposition. Mathijssen's study
evaluated a number of genes associated with the
metabolism, transport, and disposition of
Irinotecan. UGT1A1 genotype did not correlate with
Irinotecan disposition. Notable, there were only
two UGT1A1*28 patients in this study.
65
On the other hand, Paoluzzi's study showed
a significant decrease in the exposure ration of
the SN38 glucuronide to SN38, indicating a
reduction in the formation of the SN38 glucuronide
in 7/7 patients.
Font, et al., published a phase two study
evaluating the activity of docetaxel and Irinotecan
in 51 non small cell lung cancer patients.
Irinotecan 70 milligram per meter square was
administered with 25 milligram per meter square
docetaxel. The study did not see any correlation
between genotype and toxicity. The overall
incidence of grade 3/4 neutropenia and grade 3
diarrhea in this study was low. Also, the dose of
Irinotecan used in the study was 70 milligrams,
compared to 100 to 125 milligram per meter square
dose used in combination studies of Irinotecan.
A retrospective analysis of 118 Japanese
patients who received Irinotecan containing regimen
showed that UGT1A1*28 genotype was a significant
predictor of severe toxicity. In this analysis, 55
percent of the patients, irrespective of genotype,
66
who had grade 4 neutropenia also had grade 3/4
diarrhea, and 73 percent of the patients who had
grade 3/4 diarrhea also had grade 3/4 neutropenia.
Sai et al in Japan conducted a PK study to
evaluate the relationship between SN38 PK and
UGT1A1 haplotype. UGT1A1*28 was associated with
reduced SN38 glucuronide to SN38 area under the
curve ratio and increased total bilirubin.
Iyer, et al., published a prospective PK
study in 20 patients that related genotype with
reduced SN38 glucuronidation rates and lower
absolute neutrophil counts in 7/7 patients compared
to 6/6 genotype patients.
In the evaluation of the clinical data
provided to the agency for the approval of this
drug, certain predictive factors were related to
increased toxicities. These are observations only
and not statistically powered data that allowed the
agency to recommend a reduced starting dose of
camptazar for patients equal to or older than 65
years; patients who received prior pelvic or
abdominal radiotherapy, patients whose performance
67
status was two, and patients with increased
bilirubin levels.
The reduction was by only one level. That
is for the 350 milligram per meter square every
three weeks regimen, the starting dose will be 300
milligram per meter square. Similarly, if the
normal starting dose is 125 milligrams per meter
square weekly, the predictive factors will
recommend a dose of 100 milligrams per meter
square. If the patients tolerated the reduced
starting dose, the dose in the next cycle is
increased to the standard dose.
In the geriatric use section of the label
we have the statement the starting dose of
camptizar in patients 70 years and older for once
every three week dosage schedule should be 300
milligram per meter square, a 50 milligram per
meter square reduction from the standard dose.
Based on the scientific and clinical evidence
available in the current literature, the agency
believes that genotype is a predictive factor for
Irinotecan dose limiting toxicity. The agency also
68
believes that SN38 level is a likely predictive
factor for toxicity.
Based on Innocenti's article, UGT1A1
polymorphism information will help to reduce the
overall incidence of grade four neutropenia from 10
percent to 5.7 percent, almost a 50 percent
reduction in the incidence of grade four
neutropenia. Irinotecan can be given as a weekly,
biweekly or every three weeks regimen. One of the
regimens may be more appropriate for the 7/7
genotype patients. Genotype testing, combined with
bilirubin levels and other predictive factors shown
in the previous slide, will allow the physicians to
select Irinotecan therapy more judiciously in the
high risk patients. Alternate therapy, either in
the first line or in the second line setting, may
be a choice for the 7/7 genotype patients.
I'd like to thank my colleagues from the
Office of Clinical Pharmacology and
Biopharmaceutics, Dr. Larry Lesko, Dr. Shiew-Mei
Huang, and Dr. Felix Frueh for helping me out with
this presentation. I'd like to thank my colleagues
69
from the Division of Pharmaceutical Evaluation I
for helping me out with or for providing the PK
analysis of the Innocenti's and the Phase I data.
They are Dr. Roshni Ramchandani, Dr. Yanning Wang,
Dr. Brian Booth, and Dr. Joga Gobburu. I'd like to
thank my boss, Dr. Mehul Mehta, for giving me the
time to prepare for this meeting, and last but not
least, I'd like to thank my colleagues from the
Division of Oncology Drug Products, Dr. Grant
Williams and Dr. Richard Pazdur, for challenging me
to translate the principles of clinical
pharmacology, especially pharmacogenetics, to
clinical practice and clinical use.
Thank you.
DR. VENITZ: Thank you, Atik.
Any questions or comments by Committee
members?
And what I'd like to do is after each of
the presentations, give everybody an opportunity to
ask questions for clarification. We have a whole
hour reserved from 11:00 to 12:00 to discuss the
specific questions that Dr. Lesko wants us to
70
address.
So, any specific questions?
DR. GIACOMINI: Yes, I had a couple of
questions.
Was race specifically or ethnicity
specifically looked at in any of the studies that
you reviewed?
DR. RAHMAN: I would say no, because the
Japanese study included only the Japanese
population, and the other studies in Europe and the
United States included only the caucasian
population. So we at this time don't know the
prevalence in blacks, in the African-American
population, or in other populations. I think the
polymorphism is less prevalent in the Asian
population. Dr. Howard McLeod might correct me on
that.
DR. MCLEOD: There is ethnic variation for
the frequency both of the 6 and 7 allele but also
the presence of either five repeats or eight
repeats seem to be more common in the, I think, the
racial minority groups found in the United States.
71
The impact of those other alleles is not completely
clear, although Dr. Ratain may address that in his
presentation.
DR. GIACOMINI: Okay; and as a followup to
that, then, maybe you can explain it to me: what
is the difference? I mean, you've called it the
star--I think, is it 28 haplotype versus 7/7. What
is in the haplotype besides the promoters? Are
there some other snips in the haplotype, and what
are they? And are they functional in any way?
DR. RAHMAN: Dr. Howard McLeod?
DR. MCLEOD: It's a genotype, Kathy, not
haplotype. Star-28 is the name that was stuck on
the 7/7 repeat, so folks that are homozygous for
the 7/7 genotype are called star-28 by the powers
that be in determining a nomenclature for UGT1A1.
DR. GIACOMINI: So it's not like there's
any other snip in there.
DR. MCLEOD: Correct.
DR. GIACOMINI: It's just simply not.
DR. RAHMAN: Can I clarify that a little
bit? Actually, that was not an appropriate term,
72
but there was a haplotype study that has been
published by Dr. Margaret Eng's group that are
associating star-28 with other variant alleles,
star-60 and others, and there is a paper out on
that. So I kind of was alluding to that, that in
that study, the number of star-28 patients,
homozygous patients, were low, and they were
associated with other risk factors.
DR. GIACOMINI: Okay; but we can assume
when somebody says star-28, they mean the 7/7;
they're homozygous, they mean the 7/7 genotype.
DR. RAHMAN: Seven, yes.
DR. GIACOMINI: Okay; one other question:
in terms of mechanism, I didn't see you quote any,
you know, like a reporter assay or something in
which we're seeing a transcription rate difference
between the 7, some biochemical mechanism which
supports what you're seeing clinically in terms of
that. Are there biochemical data like that?
Mark's saying yes. You can't talk, Mark.
DR. MCLEOD: In the--I don't know if
everybody received--there was a packet that we
73
received of light reading. Within that is a number
of papers addressing those issues, including a
paper from Dr. Boiler Scripps that looked at both
the racial issue as well as the promoter variance
in terms of luciferase assays, seeing this stepwise
inverse relationship between length of the TA
repeat and the amount of transcript that's
produced.
DR. GIACOMINI: Okay; thank you.
DR. VENITZ: Go ahead.
DR. HALL: Can you give some idea as your
part of the agency as to your views on why, you
know, you know, several or a significant number of
the 6/6s get the toxicity, and a significant number
of the 7/7s don't get any toxicity? Do you have
some kind of rationalization for this?
DR. RAHMAN: As I've shown in this, in my
presentation that the toxicity in the 6/6s
definitely lower than 7/7 patients. As you can
see, 71 percent versus 10 percent. In one of the
studies, none of the 6/6 patients had toxicity. So
I'm not sure if there is a significant--the
74
statement that you made, there is a significant
toxicity in 6/6 patients is really true. But there
is toxicity in the 6/6 patients also, and that
could be attributed to not only Irinotecan
depending on the studies if there were a
combination of regimens used. It could be also
attributed to the others. But it also could be
attributed to Irinotecan.
DR. HALL: So have you considered other
mechanisms other than this 1A1 polymorphism as a
contributor to the toxicities?
DR. RAHMAN: Yes; as I've shown that other
predictive factors have been associated for
predicting the toxicity, like the bilirubin levels
is one of the predictors that has been kind of
alluded to being related to toxicity
DR. HALL: But bilirubin would be
metabolized by the enzymes. So they would be
somewhat correlated.
DR. RAHMAN: Yes.
DR. HALL: Other enzymes? Other genes,
perhaps?
75
DR. RAHMAN: There are papers out in the
public domain which are trying to associate other
UGT1A1 enzyme, and the factors that could also
contribute is the sensitivity of the individual
patients to specific neutropenia or to severe
diarrhea, and that is something I am not aware of
the magnitude of. But there is an understanding
that some of the patients might be overly sensitive
to a certain kind of regimen compared to the
others, even that don't carry any of the homozygous
deficient alleles.
DR. VENITZ: Jeff?
DR. BARRETT: I had a question about the
prevalence rates in your responses both in the
grade 3 diarrhea and in the neutrophil count. It
seems that there's quite a bit of interstudy
variability, and I know in your pooled analysis,
you were basing this on mean data, but is there
any--and now, with the Innocenti PK information
available, you really could use some of that
information to back-project some of the individual
variance in those models. Is that going to happen?
76
DR. RAHMAN: So, first of all, I'm trying
to address the question about finding differences
in the neutropenia and diarrhea in different
studies. What happens is that in certain trials,
the patients were allowed to take premedication for
diarrhea, so that might have helped. It is
approved in the label for using of loperamide and
other agents for controlling of diarrhea.
Now, there are two components of diarrhea.
One is the early phase diarrhea, and the other is
the late phase diarrhea. I have kind of focused on
Innocenti's article, because that truly was trying
to address these toxicity issues. And their study
was trying to look for diarrhea as well. However,
the incidence was pretty low.
Now, we are exploring the pharmacogenetics
of this drug. However, we're trying to see if SN38
could be a good predictor or could add on to to
come to a kind of dose for 6/7 and 7/7 patients,
but this is still in the earliest stage, and I
think we need some more solid data to show the
relationship and then can make a difference.
77
DR. SADEE: The star-28 genotype is
associated with Jorbert's syndrome.
DR. RAHMAN: Right.
DR. SADEE: And so my question is how
often is this diagnosed, and what is the
correlation between having a patient diagnosed with
Jorbert's syndrome and toxicity? So, in other
words, could we substitute a genotyping with a
diagnosis for Jorbert's Syndrome?
DR. RAHMAN: I haven't come across any
article to address that question.
DR. VENITZ: Larry?
DR. LESKO: Yes, just on the last
question, you know, another way to think about this
is as an adjunct test. You could actually think of
tests being done in parallel. If you think of a
screening test, you're screening an entire
population with or without an elevated bilirubin.
You could increase, I think, the sensitivity of a
UGT test by maybe screening people that signal by
their high bilirubin that they may be at potential
risk for the genotype.
78
So either in parallel or in serial, I
think you could enhance the value of the test by
thinking of it as an adjunct to the current
information that somebody would have. When you
look at--getting back to the prevalence issue, when
you look at prevalence of Jolbert's syndrome as a
function of the ethnic or racial group and the
prevalence of the UGT, there are some parallelisms
there.
In a review article that appeared last
year, the range of prevalence of UGT was anywhere
from 2 to 3 percent in Asian populations; up to 23
percent in blacks and Africans. So that's sort of
the 2 to 23 percent range that people have reported
for the prevalence of the polymorphism.
I was going to maybe add this other
information, because Atik showed the slide, and it
was shown as average values, but we were looking at
the question Steven Hall raised about the 6/6s
becoming toxic and the 7/7s not, but I think what
we have here is a probabilistic issue that if you
look at the variability in SN38 area under curve in
79
each of the genotypes, there's clear distinctions
based on mean values. However, the low end of the
6/6 area under curve and the high end of the SN38
area under curve for the 7/7s does overlap.
So I think what we're seeing, then, is
some risk in the 6/6 homozygous and some lack of
risk in the other people as one possible
explanation. I think another explanation is that
in most of these cases, more than the target allele
was not looked at, so there could be other alleles
that would be predisposing individuals to risks
that weren't measured, perhaps because of, you
know, the ethnic or racial background. But these
are some of the possible reasons anyway, but
certainly, the pharmacokinetic explanation seems to
make sense based on what we know about area under
curves related to nadirs of neutrophils.
DR. MCLEOD: Back to Dr. Sadee's question:
in the prospective study in the GI intergroup
throughout North America, the N9741 study,
Jolbert's syndrome was one of the flags in the
inclusion criteria or exclusion criteria. Yet, we
80
had an 8 percent frequency of the 7/7 genotype.
But just kind of highlights the lack of diagnosis
of Jolbert's syndrome, because it is a subclinical
benign hyperbilirubinemia syndrome.
It's out there, and so, plenty of people
are getting this drug without that diagnosis,
because it's not something that's really evaluated
in common practice.
DR. WATKINS: I was the only--as the only
hepatologist here, I'd just reiterate that it's a
subclinical diagnosis that can be brought out by
fasting and certain other conditions, like certain
protease inhibitors.
But in the studies that have looked at, I
believe, even the majority of 7/7s have bilirubins
within normal limits, so it would not be a
surrogate. I guess one question is how much does
the genotyping add in a multiple regression if you
include in serum bilirubin, which I haven't heard,
but I'm sure someone is going to address it.
DR. SINGPURWALLA: Your slide 15,
retrospective analysis, you showed two pictures,
81
one on the left, my left, and one on the right.
You have predicted versus observed. How did you
get the predicted?
DR. RAHMAN: Okay; the predicted line came
from the regression analysis.
DR. SINGPURWALLA: So the predicted is
based on the observed data.
DR. RAHMAN: Right.
DR. SINGPURWALLA: I'm curious why you
didn't fit a straight line. I know if you fit a
straight line--
DR. RAHMAN: Right.
DR. SINGPURWALLA: --it would go out, but
why did you choose that particular form?
DR. RAHMAN: It was done by our
pharmacometric folks, and they have got a better
understanding of the modeling that they did. And I
think they thought that this was the appropriate
regression to use rather than a linear regression.
DR. SINGPURWALLA: I understand, but there
were three points, and you can draw all kinds of
curves.
82
DR. RAHMAN: Yes, that's true. Actually,
the intent was to show that there is a relationship
that we have seen, but it's very soft at this time,
as I've said, because these are all the mean values
that we are lumping together; it's not the
individual ones, which would have given us a much
better fit. And also, in large clinical trials,
the PK is not collected.
So we kind of lumped them together and had
only three reliable mean values that we could do
something with predictions.
DR. SINGPURWALLA: So rather than saying
predicted, you should really say fitted.
DR. RAHMAN: Fitted.
DR. SINGPURWALLA: Because when you say
predicted, I'm thinking of some theory that tells
you what's the probability.
DR. RAHMAN: Right, right.
DR. SINGPURWALLA: As the dose increases.
DR. RAHMAN: Right.
DR. VENITZ: Ed?
DR. CAPPARELLI: Yes, I just wanted to
83
echo a little bit of what Dr. Watkins was saying,
and one of the studies you mentioned that there was
an evaluation of bilirubin levels as well as
genotype, and you'd expect them to be, you know,
highly correlated, and one of the questions is
what's the independent component that the genotype
is going to give in conjunction with the fact that
there is some induceability of this enzyme, and so,
genotype may not fully predict especially, and a
single genotype differential may not predict.
The other sort of related question that I
have is has there been any look at inducers of
CYP3A? Because the APC metabolite actually
represents a larger portion of the compound that
ends up in urine and feces. And so, if that goes
by 3A4, again, you may have some differential there
as well as if you have some inducers, you may have
some confounding of the genotype.
DR. RAHMAN: One thing I can tell you is
that there are studies going on, I think, which
Pfizer will present showing that they are looking
at, besides UGT1A1*28, other genetic factors and
84
other 3A4, 3A5 to show if--to see if they have any
association with the toxicity. So there are
studies going on. That's how far I know. But I
have not reviewed or looked at any articles
focusing on that.
And also, Dr. Ratain's and Dr. Howard's
group are looking at all these various factors in
association with toxicity for Irinotecan.
DR. DAVIDIAN: My comment just pertained
to Nozer's comment a minute ago. This is a
logistic regression, right? Is that what was done?
DR. RAHMAN: Yes.
DR. DAVIDIAN: I think it was a logistic
regression.
DR. RAHMAN: Right.
DR. DAVIDIAN: So this is just the fitted
probability curve.
DR. RAHMAN: Right.
DR. DAVIDIAN: Was this based on these
three mean values? Or was it based on--or are you
just showing the mean values on the plots?
DR. RAHMAN: It is based on the three mean
85
values.
DR. DAVIDIAN: And that's all.
DR. RAHMAN: Right.
DR. DAVIDIAN: Oh, okay.
DR. VENITZ: Okay; Atik, let me ask you
one final question for my clarification: the
Innocenti study is the only one that's a single
agent study. All the other studies are
multiagents.
DR. RAHMAN: That is correct.
DR. VENITZ: So that is really the only
study that allows us to look at Irinotecan as
opposed to the contribution that other
chemotherapeutic agents might play--
DR. RAHMAN: That is true.
DR. VENITZ: --in toxicity.
DR. RAHMAN: As far as I know, that is the
only prospective study that was actually conducted
to address this association of genotype with
Irinotecan toxicity. So this was kind of--this was
a focused study looking at these specific issues,
which was based on another phase one trial which
86
they conducted early on with 20 patients, so they
kind of, you know, expanded on that and moved on to
do this prospective trial to address the issue.
DR. VENITZ: But all the other studies
that you reviewed either prospective or
retrospective in nature, they involved other agents
as well.
DR. RAHMAN: Yes, like in the four
different regimens in the second trial that I
talked about, Markelos' trial, I think they had one
arm with a few patients who received a single
agent, Irinotecan, and then the other arms. So
there are blips of single agent here and there, but
the other studies definitely had other components
besides single agent trials.
DR. VENITZ: Okay; if there are no more
questions, then I thank you.
Our next presenter is Dr. Parodi. He is
the director of clinical pharmacogenomics at
Pfizer, and he's going to give us the Pfizer
perspective.
DR. PARODI: Good morning.
87
I would like to thank Dr. Lesko, Dr.
Rahman for inviting Pfizer to participate in this
meeting. I would like also to acknowledge my
colleagues Dr. Mark Morrison and Dr. Akitunde Belo,
who are here to answer any questions that may be in
regards to clinical or pharmacokinetic issues
during the meeting.
During this presentation, we would like to
reiterate the commitment of Pfizer to the safety of
all of our products. In addition, we would like to
talk about how we are applying pharmacogenetics at
Pfizer. At Pfizer, pharmacogenetics is getting
important information during the whole drug
development process, from early discovery research
through development and through the safety and
efficacy of our marketed products.
Today's discussion is around Irinotecan, a
cytotoxic agent that has been proven to be an
effective therapeutic choice for patients with
metastatic colorectal cancer and colorectal cancer
in general. Since the late nineties, there have
been several publications reporting a relationship
88
between Irinotecan's safety and genotype. We have
kept abreast of these publications, and we have
provided for the Advisory Committee a summary of
those published reports in the background document.
We will review this data, and we will
present to a highlight of what Pfizer is doing to
continue to expand the database regarding the
Irinotecan pharmacogenomics. We will also talk
about how we're working in collaboration with the
FDA to provide useful information in the label that
may refer to this particular genotype.
We believe this forum is going to be an
important meeting, where we can share our views and
our ideas about the subject and present activities
that we are currently undertaking to address these
issues. I would like to outline how
pharmacogenomics is being used at Pfizer. At
Pfizer, we use pharmacogenomics as a generic term
which also encompasses what may be traditionally
called pharmacogenetics. We use disease genetics
to select targets. We use the knowledge of the
variation of our targets to improve the safety and
89
efficacy profile of our drug candidates. And in
some cases, we are using the genetic variation to
define subpopulations for conducting proof of
concept studies.
For our marketed products, we are also
looking into the effect that genetic variation has
on the safety and efficacy of our drugs. Today,
we're focusing on the effect of genetic variation
on the safety and efficacy of Irinotecan.
We have been interested in this area since
the first studies that were reported reporting the
relationship between Irinotecan safety and
genotype. Later, Dr. Ratain, who has been a leader
in this effort, will address and present his ideas
on the subject.
During recent years, we have supported and
sponsored many clinical trials that contain a
pharmacogenomics component. We will go through a
detailed list of the projects we are supporting or
sponsoring later in the presentation. Most
recently, we have engaged in a collaboration with a
company in Germany called Epidaurus to explore the
90
significant variation of transporters in
metabolizing genes in pharmacogenomics.
Today, we will focus on our knowledge of
the variation in the genes involved in the
Irinotecan disposition and metabolism. This is a
representation of the genes involved in Irinotecan
metabolism, taking into account only what's going
on in the gastrointestinal lumen, where we have
more information. We have very little information
regarding the genes involved in the disposition of
both Irinotecan and its metabolites, both at bone
marrow level or at tumor level.
In general, we can say that the mechanism
for disposition and metabolism of Irinotecan is
complex, and it involves several genes. We want to
also note that all of these genes are very
polymorphic, and those polymorphisms are known to
be functional. As pointed out earlier, there is a
great deal of variability in the frequency of the
different alleles of these genes in the different
ethnic groups, which makes extrapolations from one
ethnic group to another very difficult.
91
The UGT1A1 polymorphisms are probably the
best known, but information is constantly being
accumulated about the polymorphisms in other genes.
As recently as a couple of weeks ago, there has
been a couple of reports reporting on novel
polymorphisms in the carboxylesterase genes.
Our discussion today will focus on one of
these genes, UGT1A1, in particular, one snip in one
of these genes, and we would like to address the
relevance of the published data associating that
polymorphism, specifically what has been called the
7/7 or star-28 polymorphism, in regards to
neutropenia and diarrhea.
By now, you are familiar with these
studies. We have basically conducted an extensive
review of the published literature and have
selected these studies which are full papers,
because they provide the frequencies of diarrhea
and neutropenia as well as the frequencies of
genotypes for the UGT1A1 gene.
Something we would like to note is that
these studies contain a rather small number of
92
individuals included in the studies. Given the low
frequency of the 7/7 genotype, very few patients in
this group have been actually included in these
studies.
Again, all studies don't include the same
type of cancer patients. Two of these studies
include only colorectal cancer patients, while the
other three include primarily lung cancer patients.
Probably more significantly is the issue that these
studies all use different dosing regimens, both in
the intensity of the dose of Irinotecan and the
schedule, and more significantly yet, the inclusion
of 5-fluorouracil, a known agent that causes
neutropenia.
Although there are many differences in
these studies, we have attempted to look at the
data in a comprehensive way. So we realize that
this data can be interpreted from multiple
perspectives, so what I'm going to provide for you
in the next few slides is a statistical analysis of
the data. All of the analysis has been done based
on the raw data presented in those papers and are
93
unadjusted for any known factors.
First, we would like to look at the rate
of neutropenia in the UGT1A1 7/7 patients compared
to the rate of neutropenia in the group containing
the 6/6 plus the 6/7 patients. A simple look at
this table tells us that the frequency of
neutropenia in the 7/7 patients is higher than the
frequency of neutropenia in this other group. In
order to establish a comparison between the
different rates recorded in the studies, we
calculated the odds ratios and the 95 percent
confidence intervals as represented by this
statistic to quantify the association between
genotype and neutropenia.
The odds ratios vary from study to study
and have very wide confidence intervals. Based on
the 95 percent confidence intervals, the odds ratio
was statistically significant in three out of the
four studies.
Without adjusting for known risk factors,
this univariate analysis shows a statistically
significant association between UGT1A1 7/7 genotype
94
and neutropenia, although we note that the
association varies among studies with odds ratios
between 2.5 and 16.7. This variability could be
due to the small sample size, differences in the
dosing schedules and the contribution of
5-fluorouracil to neutropenia; the fact that we are
not controlling for known factors such as baseline
bilirubin levels, age, performance status, and
prior pelvic radiation; and indeed, differences in
the population's treatment, both from the ethnic
perspective and also from the tumor type.
In a similar fashion, we have done the
same analysis for diarrhea, grade three plus. In
this case, we have included the Font study, because
the Font study reports the rates of diarrhea for
the different genotypes. It was not included in
the analysis of neutropenia because Font did not
provide the data for neutropenia separately in his
publication.
Again, we would like to note that this
analysis has been done without adjusting for known
factors, and if we look at the diarrhea rate
95
between the 7/7 genotype and the group of 6/6 plus
6/7, simple inspection of the rates shows that it's
difficult to draw a general conclusion. Here
again, we calculate the odds ratios and 95 percent
confidence intervals as a representative statistic
to quantify the association between genotype and
severe diarrhea.
The odds ratios vary from study to study
and have wide confidence intervals, and based on
the 95 percent confidence intervals, we can say
that two out of five studies were statistically
significant.
In summary, we have performed a
comprehensive review of the published literature
and selected publications that provided genotypes
and rates for neutropenia and diarrhea in
Irinotecan-treated patients. Although there are
significant differences among studies, we analyzed
the data without adjustments using odds ratios and
confidence intervals as a representative statistic.
We conclude that there is a statistically
significant association of UGT1A1 genotype in the
96
development of neutropenia. The association of
genotype in diarrhea is not as consistent among
studies.
Now, if we want to translate this
association data to a predictive performance of a
test, we need to assess multiple parameters. We
have used the same published rates for neutropenia
in genotypes used for the association analysis to
calculate the test performance parameters.
The following analysis assumes that the
genotyping test is 100 percent accurate for the
detection of UGT1A1 7/7, 6/6 and 6/7 genotype. We
have calculated the performance parameters based on
the reported rates in the publications that were
examined previously for neutropenia.
First, we look at the clinical
sensitivity. The clinical sensitivity can be
interpreted as the probability that those patients
that have neutropenia will have the 7/7 genotype.
We note that the clinical sensitivity varies from
15 percent or 0.15 to 50 percent.
Probably for our discussion, it's more
97
important to look at the predicted values.
Ideally, we would like to have a test with high
predicted values, maybe approaching 100 percent
possibly. Under the assumption that we know that a
patient has the 7/7 UGT1A1 genotype, the overall
probability that the patient will develop
neutropenia will be about 50 percent.
These values are not highly predictive for
developing neutropenia. Given that we cannot
accurately predict the development of neutropenia,
we have to be cautious when balancing the risk for
neutropenia and the benefit of treatment.
Neutropenia is generally manageable, and dosing
reductions for all UGT1A1 patients would result in
unnecessary reductions for 50 percent of the
patients, and the outcome is unknown.
We think that this data furnishes a
provocative signal hinting at the biology and
provides guidance for additional ongoing research
in this area. We recognize the importance of this
data that has been collected so far, but we also
feel that more research is necessary. As mentioned
98
earlier, we have many ongoing sponsor and supported
trials that investigate the UGT1A1 and other
genetic factors and their association with severe
neutropenia and diarrhea. In parallel, we have
ongoing discussions with the FDA to understand the
implications of the published data and what may be
an appropriate use of this data in the Camptosar
label.
These are the sponsored or supported
studies that include Irinotecan-treated patients
and that have a pharmacogenomics component. These
studies may address some of the limitations of
previous published studies, in particular, sample
size, the analysis of multiple genetic factors, the
possibility for controlling for known factors, and
the inclusion of current standard of care regimens
for first line metastatic cancer or colorectal
cancer patients FOLFIRI and FOLFOX.
Although most of these studies are
ongoing, we would like to highlight that study
N9741 is finished, and the NCCTG has almost
completed an analysis of pharmacogenomics data for
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15 polymorphic markers on 10 genes. A publication
is planned in the near future by the NCCTG.
The future looks very promising. The data
from these studies will provide important new
information in addition to other efforts and other
studies that are being conducted by other
investigators. We hope that from these studies, we
can better define the magnitude and strength of the
association between UGT1A1 and safety; we can also
identify other potential covariants of severe
neutropenia and diarrhea, and as the data matures
from the ongoing studies, we look forward to
providing additional information for health care
providers and patients to aid their treatment
decisions.
I would like to acknowledge a large team
of Pfizer colleagues who have worked together to
provide this presentation this morning. Thank you.
DR. VENITZ: Thank you.
Any questions, comments by Committee
members?
Can I ask you to go back to your slide
100
where you discuss the performance of the test? You
focus on the sensitivity. Would you care to
discuss the specificity and the negative predictive
value?
DR. PARODI: The clinical specificity
basically gives the overall probability that given
that a patient has neutropenia, does not have
neutropenia, will not have a 7/7 positive test. In
general, the clinical specificity seems quite high.
The negative predicted value gives a probability
that given that the test is negative for 7/7, what
is the probability that that patient will not
develop neutropenia?
The overall values that you see there are
averages. They are not weighted averages. We feel
that a negative predicted value is relatively high
and much better than the positive predicted value.
DR. VENITZ: So would it be fair, based on
this analysis, then, to say if you did the test on
a large number of patients, you may not necessarily
predict neutropenia with a 50 percent sensitivity,
but if your star-28 is negative, you have a very
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small chance of developing neutropenia?
DR. PARODI: Certainly, if you get a
negative value--a negative test for 7/7, you have a
high probability of not developing neutropenia than
if you had a positive value for 7/7; basically, a
50 percent chance of developing neutropenia is
equivalent to a toss-up.
DR. VENITZ: Right, but that's from your
perspective the bad thing, but the good thing is,
on the other hand, if you have a negative test,
you're unlikely, very unlikely, to develop
neutropenia; is that correct?
DR. PARODI: That is correct, but overall,
given the incidence of neutropenia, the likelihood
that you will develop neutropenia anyways is low.
DR. VENITZ: Any other questions?
Yes?
DR. SINGPURWALLA: Yes, I was just looking
at your first slide where you had the odds ratios
and the confidence limits around the odds ratios.
DR. PARODI: Which one? For neutropenia
or diarrhea?
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DR. SINGPURWALLA: Well, let's just take
that one.
DR. PARODI: Okay.
DR. SINGPURWALLA: I can't pronounce all
these things.
DR. PARODI: Oh, me neither.
DR. SINGPURWALLA: So let me try and
understand the objective of this slide from a
layperson's point of view.
DR. PARODI: Right.
DR. SINGPURWALLA: If I was 7-7, and if I
took this medication, then, it appears that there
is a 50 percent chance that I'll get an adverse
reaction; is that correct?
DR. PARODI: That is correct. You have a
higher probability of having an adverse reaction.
DR. SINGPURWALLA: And if I was either a
6/6 or a 6/7, I have a lower probability.
DR. PARODI: That is correct.
DR. SINGPURWALLA: If I pool all those
numbers, I find the answers to be 50 percent
probability and 25 percent probability roughly, if
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I just add everything now.
DR. PARODI: Yes, yes.
DR. SINGPURWALLA: So I'd still be scared
if I had a 25 percent chance of an adverse
reaction.
DR. PARODI: Yes, and you should be.
DR. SINGPURWALLA: Is that the point
you're making?
DR. PARODI: The point we're trying to
make is we try to really provide--we'd have liked
to have done a meta-analysis of this data. Given
the differences, significant differences in these
studies, it's really unfair to pool all this data
together in a meta-analysis exercise. So we are
basically presenting this data in a tabular form,
using a calculated statistic as a comparator
between studies, because not all studies reported
the same statistic, as Dr. Rahman indicated. I
mean, some people used one statistic; some the
other.
So it made the tabulation and the
comparison between studies a little bit difficult
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but--
DR. SINGPURWALLA: I see your point, but
look at the confidence limits. They're so wild.
DR. PARODI: The confidence limits are
very wide, and that is primarily due possibly to
the fact that these are very small sample sizes.
DR. SINGPURWALLA: That's right.
Therefore, it makes sense to pool them.
DR. PARODI: It makes sense to pool them,
but, I mean, we're doing this in a highly
abstracted way, because I think pooling the data is
really not warranted. This is basically an
exercise, and also, we have not adjusted for known
factors, because it is difficult to extract from
the policy literature what was the performance
status of the patient, what was the baseline
bilirubin. All of these adjustments will have to
be made, since these are known covariants in the
incidence of neutropenia.
DR. SINGPURWALLA: Can I suggest that you
consider the use of prior odds and the posterior
odds in these kinds of studies?
105
DR. PARODI: Can you be more explicit?
DR. SINGPURWALLA: Well, prior odds are
you put prior distributions on these ratios, and
you compute the aposterior using these.
DR. PARODI: Okay; prior probabilities
and--
DR. SINGPURWALLA: Right.
DR. PARODI: We could do something like
that.
DR. PAZDUR: I wanted to bring up some
clinical issues here, and perhaps I realize that
the company Pfizer kind of got this drug from
Pharmacia, who did most of the development on this,
and feel free, obviously, to discuss these with
your clinical colleagues--
DR. PARODI: Right.
DR. PAZDUR: --if they have an issue with
this. But I think it's very important for the
Committee here to understand the clinical
development of this drug, and obviously, we'll be
talking about an effect on dose reduction and
potentially a potential reduction in efficacy. And
106
I wanted to give the Committee some idea about how
the dose of this drug was selected on either
schedule. There's two schedules on the product
label: a weekly schedule times four and then an
every three weeks schedule.
How is that dose selected in the 1990s
here? And that has carried us forward here
throughout the entire clinical development, and I
was wondering if you could give us some idea: how
did you get this dose? What was it based on?
DR. PARODI: I would like to defer to one
of my colleagues to answer that particular
question.
MR. MORRISON: Okay; thank you. I'm Mark
Morrison. I'm the medical team leader for
Camptosar in the U.S. I've been with Pfizer, so I
don't have first hand experience of the development
at Pharmacia; however, the dose was arrived at by
the standard mechanism of looking at MTD and
pushing the dose up to the MTD and then backing
down to a tolerable dose just below MTD. So it was
a standard development.
107
DR. PAZDUR: Well, I guess the point that
I wanted to bring out here, when the dose was
selected, we were looking in a 5-FU refractory
population, and the dose was being looked at in
terms of response rate here, okay, which was
relatively modest. We were looking at 15 percent
response rate. And the point that I want to bring
out is what is the relationship that the company
has with dose and a clinical outcome of an impact
on survival? Because here again, if we talk about
perhaps changing the dose, you have to be cognizant
about any missing data that we have on a dose and
the ultimate clinical outcome and what is that
level of certainty that we have regarding that
dose, the package insert dose and clinical outcome?
MR. MORRISON: That's actually something
that we proposed to look at going back into the
databases. What we do know, in the first line
setting, we use a combination of bolus IFL is that
with dose reduction after cycle one and follow them
out, each group is dose-reduced, and you do see a
slight trend for a difference in efficacy; however,
108
it's not statistically significant, so that you'd
have to come to the conclusion that the overall
efficacy at the end of the day was very similar,
because both wind up being dose-reduced more.
We do need to look at that in the
single-agent setting going back to the second line
studies. One thing I'd like to point out, if we go
back to the probability slide, looking at negative
predictive value, I think a very important point to
make in looking at the label, the incidence of
grade four neutropenia would be expected if you
average the two trials, which isn't statistically
valid, because they're two different populations,
but it comes out to about 18 percent.
So the negative predicted value tells you
that you have a 17 percent chance of having the
effect or an 83 percent chance of not having the
effect, and that's what we know to begin with. So
the test actually is more indicative of the
standard population. The positive predictive value
of 50 percent gives us added information that these
patients are at increased risk over the general
109
population; however, we would like a test with a
positive predictive value of 90 or 95 percent.
So what other factors are coming into
play? Is it the carboxylesterase, for example? Is
it transporters? Camptosar itself is present in
micromolar concentrations versus SN38 in nanomolar
concentrations.
So given the difference in efficacy
between the two compounds, they're both present at
therapeutic concentrations, and UGT is important
for SN38 much more so than for Camptosar, and the
carboxylesterase may be a very important factor.
We don't know whether it is; upcoming data from our
clinical trials will hopefully give us an answer,
and likewise, transporters in the bone marrow and
in the gut and in the liver may help us unwind the
story of selectivity and look at the therapeutic
index and try to figure out what combination of
factors might give us a positive predictive value
greater than 90 percent.
So we're striving to do that, and we will
have data available in the near future from a
110
number of trials that Dr. Parodi has mentioned to
try to improve on that ratio.
DR. PAZDUR: Just one last question. We
spent a lot of time on this slide. I've seen it
put up now three or four times, and it addresses
severe neutropenia. However, you know, if you ask
medical oncologists that actually use this drug, if
you ask them what are the top 10 toxicities with
Irinotecan, one to nine would be diarrhea,
diarrhea, diarrhea, diarrhea, diarrhea, diarrhea,
diarrhea, diarrhea.
So is it really a fair--just to look at
neutropenia here, are we really missing something
by not really looking at what is the most
clinically relevant toxicity, and that is either
diarrhea alone which leads to the hospitalization
or, more importantly, diarrhea in the presence of
severe neutropenia, which generally is very
problematic and is usually associated with the
deaths that we have seen on this drug?
So I would like to make sure that the
Committee understands, you know, the clinical
111
relevance of neutropenia that we're talking about
here. Severe neutropenia in oncology circles, we
deal with on a daily basis here. The real toxicity
with this drug that we should be paying attention
to is diarrhea and severe diarrhea that will lead
to the patient's hospitalization.
One last question, just to give the
Committee an idea of kind of the softness on the
dosing on this drug. If one would take a look at
the single agent use of Irinotecan before it went
into combinations, at the labeled doses of 125
milligrams per meter squared, how many people could
actually be maintained on that full dose?
MR. MORRISON: I think the dose intensity
for the various drugs ranges from about 70 to 80
percent.
DR. PAZDUR: Okay; but how many people
would require dose reductions, I'm asking
basically?
MR. MORRISON: By cycle two, I know in the
IFL data, for example, in first line--
DR. PARODI: Single agent.
112
MR. MORRISON: Yes, single agent, I don't
have that figure.
DR. PARODI: It's usually the majority,
usually a high, high number of people.
MR. MORRISON: And if I could comment on
the diarrhea issue, this is something we're
absolutely looking at, and we're very concerned
about neutropenia occurring in the presence of
diarrhea when we've got endothelium or epithelium
is compromised. And we would like to see what
correlates with diarrhea, and I think more
importantly, we're urging the medical community to
use the infusional regimen of 5-FU, which has been
shown to cause less diarrhea and actually seems to
be more efficacious.
So we're actually advocating use of the
FOLFERI regimen, which is a two-day infusion of
5-FU preceded by a bolus of 5-FU, and the
Irinotecan and 5-FU are given once every two weeks.
So that seems to be a much more tolerable regimen;
requires less dose reduction; and appears to be
more efficacious, and we are looking at these same
113
pharmacogenomic correlates for UGT and a whole host
of other genes with that regimen in our ongoing
trials.
DR. WATKINS: Just a quick point, which is
obvious to everybody, I'm sure, on the panel here.
But as a newcomer, it obviously would be very nice
if the genomic DNA and the clinical data was
available on the patients who went through the
studies back in the early nineties, that would
greatly be to patients' benefits. And I guess
since you started off the talk talking about
Pfizer's global role in pharmacogenetics and as a
leader in R&D, is Pfizer now routinely collecting
genomic DNA and creating databases and bank so that
when such questions come up in the future for
drugs, you can very quickly go back and--
MR. MORRISON: Yes.
DR. WATKINS: --verify these rather than
doing large phase four studies?
DR. PARODI: Absolutely. We have a very
large commitment in the company to
pharmacogenomics, including systematic collection
114
of DNA samples, and we are actually developing the
right infrastructure to store and retain this
valuable asset for future investigations.
MR. MORRISON: And we're actually looking
at this not just in terms of Camptosar, but we're
looking at genes involved in a number of other
compounds as well. We're looking at genes involved
in metastasis; for example, in a protocol that
we're just getting ready to launch, we're going to
have tumor samples from the primary tumor and from
liver metastases in a neoadjutant program.
So we're looking at genes that are
involved in invasion metastasis and responsive
therapy, so we're trying to look at everything
across the gamut.
One thing I neglected to mention was we're
also looking very carefully at bilirubin levels,
and we do have in our label a statement concerning
data looking at bilirubin in the normal range,
even. In the range of 1.0 to 1.5 milligrams per
deciliter, there is a significant increase in
toxicity. And that is within the label, and it's
115
brought to clinicians' attention.
And this is statistically significant
compared to patients with bilirubins less than 1,
so we're very concerned about this. And we would
like to see how bilirubin correlates with UGT, and
maybe Luis can comment more on that, because I know
in the analysis by Dr. Innocenti, that was
addressed.
DR. VENITZ: Steve.
DR. HALL: Yes, I noticed on your initial
slide talking about the metabolism of the drug and
its metabolites that only the UGT1A1 was mentioned.
And that seems to be the theme so far.
Now, there's a growing literature, and
Kathy's just done a literature search here on the
computer that, you know, other UGTs are involved,
and in your own materials that you supplied to us,
there was a study from the Foxchase Cancer
Institute, I think, that implicated for sure the
1A7 UGT also as a contributor.
So I wondered if you had any information
on the impact of the other UGTs, and secondly, I
116
noticed in the list of genes that you plan to look
for in the studies you listed again in your
materials, there were no other UGTs mentioned, and
I wondered if that was something that in the
short-term, you would be able to get some concrete
insight into rather than in the longer-term
studies.
DR. PARODI: I think we have, as I
indicated, sponsored the N9741 study, which has
established a collection of DNA samples from
Irinotecan-treated patients. And maybe there is an
opportunity in using those samples to investigate
other candidate genes that may be associated with
outcomes.
In our earlier studies, we had not
collected a DNA sample from the earlier
registration studies, but as I indicated in another
slide, we had on the other collaborative studies
that we're conducting right now, we are collecting
samples for future analysis. So if we wanted an
answer about, well, what about UGT1A7, I think a
more immediate answer can come from maybe
117
genotyping those samples from the 9741 and getting
an answer.
Maybe Dr. McLeod would like to comment on
that.
DR. MCLEOD: In the context of several of
the GI intergroup studies which I am involved in as
well as several others in this room, Dr. Ratain,
Dr. Giacomini, we have tried to take a drug pathway
approach that does not focus on any one particular
element of the disposition of the drug. And so,
missing from this slide here is also many of the
pharmacodynamic markers that are starting to come
out of the some of the screening systems we have.
And so, taking this pseudoholistic
approach as much as our knowledge lets us, we're
trying to understand these issues. So any genes
that come out of these screens are fair game and
hopefully will complement the additional data
that's available.
DR. SADEE: I just want to bring up the
issue of how we use genotype and also as a question
on this. Obviously, and just looking at the 6 and
118
7 alleles for the gene, including the enzyme, we
will have three genotypes. One is you get both
7/7; that's homozygous for one; and then, you have
homozygous for 6/6; and then, you have the third
population that's heterozygous.
Now, you have chosen, in most of your
slides, to combine the homozygous 6/6 with the
heterozygous 6/7. And in this particular case,
it's very likely that there is additional
functional polymorphism in this gene. So you have
a much greater chance for a large variety in the
heterozygous population that you included with the
6/6 or the 6/6 and the 6/7. They're very
different. And you also have, in the 6/7
population, clinical symptoms for--suggesting that
this is truly, again, a different population.
So my question is how do we deal with, if
we make dosage recommendations, and we have one
population where it's very uncertain; we have one
population--that would be the heterozygous
population; one where it's--and the two others are
more certain, I would say, or we have better
119
predictors.
So can we actually combine them, those
populations, heterozygous and homozygous, and would
that be a basis of making decisions along the lines
of dosages?
DR. PARODI: The reason which we combined
6/6 and 6/7s was basically because we saw that
those groups, at least in the reported data,
behaved almost equivalently. So from the phenotype
that we're looking at was almost indistinguishable.
So that was the reason why we--of course, when
you--I take your point that even within one of
these genotypes, like the--even including the 7/7,
it can be genetically very heterogeneous, because
any of these groups can be genetically
heterogeneous.
But from the point of view of the
phenotype, it certainly made sense to us to combine
6/6 and 6/7s and compare that to the 7/7s.
DR. LESKO: Yes, it's really two questions
with regard to the information provided. The first
is thinking about risk factors separately versus
120
complements. You mentioned there appears to be a
relationship, albeit imperfect, between
pretreatment bilirubin levels and the level of
toxicity and neutropenia, and that's consistent
with the literature. There's been several articles
that have pointed in that direction with modest
predictive values, let's say.
However, if I were to--and this may be
something that's worth calculating--if I were to
take individuals with certain preexisting bilirubin
levels and then add to it as a complement the
genotype information, would I then increase
predictive value in terms of my risk of toxicity,
my individual risk of toxicity, to the point where
it would be higher than it is?
That would be sort of the one question,
and one could go back and look at that, I'm sure,
with the data in the files, and taken together,
those two indicators, I think, would give a pretty
good indication of an individual's risk of
developing toxicity.
The second question is with regard to
121
dosing. I mean, from our discussions, it's clear
that dosing in the label is based upon some
clinical studies, but there's also, as I recall,
some dose reductions recommended in the label. And
I don't have it in front of me, but I think elderly
was one of those. And there's some measure of dose
reduction in the elderly. And I'd wondered if
there's any information on either--well, the
information on what was used to lower that dose,
and is there any exposure data in elderly that
would be related to the exposure you would see in
genotype?
In other words, I'm trying to draw an
analogous situation between lowering the dose in
terms of elderly, because they have a certain
exposure of SN38 area under curve and then
comparing that to the area under curve that we see
in the genotypes and see if there's any logic to
using that as a guide to what dosing reductions
would be done.
DR. PARODI: If I can answer the first
question, and maybe Dr. Morrison can answer the
122
second, with regard to the correlation between
baseline bilirubin levels and the neutropenia,
actually, the Innocenti paper models this
correlation and actually, in the electronic version
of the paper, they offer to deposit the data at the
publicly available genomics database.
I have checked the database, and it was
not publicly available yet. So it might become
available. And then, once that data is available,
we could attempt the modeling. They report a
multivariate analysis adding a genotype with
baseline bilirubin, and in their modeling, both
genotype, baseline bilirubin and sex were
determinants of the correlation.
MR. MORRISON: Regarding the second
question, I can't comment on exposure to Irinotecan
or SN38; however, the decision to use clinical
judgment to perhaps decrease the dose level in the
elderly was based on an increase in late diarrhea
that was seen in that population.
DR. PAZDUR: But didn't Upjohn do a study?
Perhaps Dr. McGovren could comment on this, on the
123
elderly, and it had a PK component?
DR. MCGOVREN: Yes, yes.
DR. PAZDUR: And I believe I was one of
the authors on that.
[Laughter.]
DR. VENITZ: Would you introduce yourself,
please?
DR. MCGOVREN: For various reasons, that
data has been a long time being put into a report
form, and--
DR. PAZDUR: Yes, I know that.
DR. MCGOVREN: And in fact, that data will
be filed with the agency very soon. Age is
probably not the best example to go into here,
because in fact, in that study that you
participated in, there really was no association
between age and diarrhea or age and PK.
DR. VENITZ: Can you introduce yourself
for the record?
DR. MCGOVREN: I'm sorry; it's Pat
McGovren from clin pharm group at Pfizer.
DR. PAZDUR: And for the record, that long
124
time was how many years?
DR. MCGOVREN: It was probably about five
or six years, yes.
DR. VENITZ: Okay; thank you.
DR. MCGOVREN: For the record, do you want
to indicate what that gesture means?
[Laughter.]
DR. VENITZ: Speaking about the record, I
think it's time for a break. We'll take a break
until 10:45 and reconvene for the Committee
discussion. So at 10:45, we'll reconvene.
[Recess.]
DR. VENITZ: Okay; welcome back, everyone.
Our next and last speaker for our first topic is
Dr. Mark Ratain. He is one of the authors of the
paper that was discussed in detail earlier on, and
he's going to give us his perception and
perspective as to how to use the test for
UGT1A1*28.
DR. RATAIN: Good morning. Thank you. I
very much appreciate the opportunity to speak here.
I want to thank Dr. Lesko and Rahman from FDA for
125
inviting me. I really want to thank Pfizer and
their predecessor companies for providing drug for
my trials. Actually, it goes back into the early
nineties with our initial trial. And I thank the
indulgence of the Advisory Committee.
Some of you are totally overexposed to
Irinotecan already.
[Laughter.]
DR. RATAIN: And that goes long before
this particular meeting.
Now, I've been working on this drug since
the early 1990s, and I was specifically asked today
to speak to you as a clinician, as a medical
oncologist, and how I would see from with obviously
a biased view how this test could be used to
enhance the treatment of patients.
So, many of you have seen a poster child
before. The poster child is the one on the right
here, 6-mercaptopurine. And you're very familiar
with this, as was alluded to in the important work
that's been done by many, particularly the group at
St. Jude, and this is a figure from the Nature
126
Reviews cancer paper by Mary Relling and her
colleague showing the relationship of TMPT
polymorphisms to the therapeutic index of
6-mercaptopurine in children with acute leukemia.
Now, here's another poster child. This is
from pharm GKB. This is the Website of the NIH
pharmacogenetics research network, and this was our
poster child. This was the first pathway that went
up. This is a pathway that some members of this
advisory committee have agonized over, and I would
urge you to take a look at it. It is a clickable
interface. And in theory, it should get you the
data that you're looking for; at least that's what
we're told. Some of us have actually been able to
retrieve the data out of this database.
But I think it's pretty clear that this is
a very complex drug. You see the parent drug here.
The parent drug is inactive. The only way the
parent drug becomes active is when it's hydrolyzed
by carboxylesterases, and there are
carboxylesterases within cells. So you can, if you
expose cells to Irinotecan and the cells contain
127
carboxylesterases, the drugs will get hydrolyzed to
SN38 and become activated. But by itself, it is
inactive. And the primary enzyme responsible for
the hydrolysis is CES-2.
Irinotecan is also a substrate, as shown
here, for CYP-3A. Both CYP-3A4 and CYP-3A5,
although CYP-3A5 has a relatively minor role; the
major oxidative metabolite is APC. That is formed
only by CYP-3A4, and I will add we have looked at
CYP-3A polymorphisms in our studies. We have not
been able to correlate it with anything.
SN38 is a substrate for glucuronasil
transferases. As far as the glucuronasil
transferases that are expressed in the liver,
UGT1A1 far and away is the most important enzyme.
There is probably a minor contribution of UGT1A9.
We have not been able to demonstrate any role for
UGT1A6 in the metabolism of SN38.
And there are other UGT1s that are
expressed in the gut, particularly UGT1A7 and
UGT1A10 that do have the capability of
glucuronidating SN38.
128
And finally, SN38 as well as the parent
drug and the glucuronide are all substrates for a
variety of transporters, and we are actively
looking at the relationship of polymorphisms in
these transporters to the pharmacokinetics and
toxicity of the drug. We have not been able to
find any relationship between polymorphisms and
MDR1 or ABCB1 and clinical outcomes, but we have
some preliminary data that was presented at the
American Society for Clinical Oncology meeting this
year on a polymorphism in ABCC2, also known as
MRP2, and the pharmacokinetics plasma
concentrations of parent drug as well as APC and
SN38 glucuronide, and we currently have some work
in progress looking at possible relationships of
subtleties such as haplotypes and other clinical
outcomes, but that is all work in progress that has
not even undergone any internal statistical review.
So I really want to focus you on the
subject of today, UGT1A1. Because as you've heard,
this is a polymorphism that, one, is common, and
two, for which there have been multiple studies.
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Now, this is a study, and I can't remember whether
this was a pharmacy or an Upjohn study, the mass
balance study of Irinotecan. And I think that this
paper, published in Drug Metabolism and Disposition
in 2000, gives you some idea of what happens to the
drug.
And in a mass balance study, 55 percent of
the drug is found, is excreted as parent drug.
Nine percent is SN38; 3 percent is SN38
glucuronide. Only 11 percent is this oxidative
metabolite APC. Only 1.5 percent as NPC, another
oxidative metabolite. So as far as metabolites,
you can see that this pathway, down SN38 and SN38
glucuronide is pretty important, but also, there's
a lot of parent drug that comes out unchanged,
which does make you wonder about the importance of
polymorphisms and transporters.
Now, as you've heard, Irinotecan is a
cytotoxic agent approved in the United States for
metastatic colorectal cancer. It is usually
administered these days in combination with 5-FU,
and I will add is also active in many other
130
malignant diseases, and it's commonly used
off-label for other solid tumors.
Its usage is definitely limited by
toxicity, both actual toxicity and perceived
toxicity. The toxicities include life-threatening
neutropenia and associated infection. This appears
to be most common on the every three week schedule.
And the other major toxicity, clearly the one that
is more problematic when it occurs, is severe or
life-threatening diarrhea, requiring parenteral
fluids and/or hospitalization, and this occurs
primarily on the schedule, the weekly schedule,
which consists of four weeks on, two weeks off.
And in our hands, at least, this diarrhea
really is not very common on the every three week
schedule. So clearly, we have different
pharmacodynamics going on on these two different
schedules. And so, it is very important not to
lump studies together, particularly when looking at
the diarrhea, because of the schedule-dependent
effects, as well as the confounding issue of
concomitant drugs such as 5-FU, which commonly
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causes diarrhea.
Now, I think from a clinician's
perspective, Irinotecan is one of many FDA-approved
choices for metastatic colorectal cancer. And the
discussion to date has focused on if one chooses to
give Irinotecan, what does one do? And I think
from a clinician's perspective, one has to also ask
the question: might genotyping help the clinician
decide among the various choices?
So for first-line therapy, you have 5-FU,
which nowadays is always given with leucovorin,
folinic acid, a modulator of 5-FU, Irinotecan,
oxaliplatin, which is a platinum analogue that has
a totally different mechanism of action from any of
the other approved drugs; capecitabine, which is an
oral fluoroprimadine and is very similar to 5-FU,
and bevacizumab, Genentech's monoclonal antibody
against veg-F. And these are all approved for
first-line therapy in various combinations.
For second-line therapy, one has a choice
of Irinotecan, oxaliplatin, 5-FU with leucovorin,
or cetuximab, the monoclonal antibody against EGFR
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marketed by Inclone and Bristol-Myers-Squibb. So
again, one has many choices.
So how might clinicians choose among
various choices? Well, one is clearly personal
experience. Two is interpretation of phase three
data; three, marketing influences; four,
reimbursement; five is a very controversial piece,
chemosensitivity testing. There was a recent story
in the Wall Street Journal suggesting that this
should be done. The American Society for Clinical
Oncology has reviewed this and really, there are no
good data as to how one might use chemosensitivity
testing in an infectious disease kind of model to
decide among treatments. And then, the one we're
talking about today, genotyping, whether one can
predict toxicity or one can predict activity or
efficacy. These might influence how a clinician
would choose among the various options.
So I want to review with you some of the
clinical data, so you can see the dilemma. So this
is a study from the North Central Cancer Treatment
Group, and this was a prospective randomized study,
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three different regimens: N9741. And you see that
two of the regimens, IFL and IROX, included
Irinotecan, and one regimen, FOLFOX4, did not
include Irinotecan.
And this study demonstrated that the two
Irinotecan regimens were both--that FOLFOX4 was
superior to IFL, p value 0.0001, and that IROX was
superior to IFL, so that the conclusion of many
clinicians from this study was that FOLFOX4, a
regimen that does not contain Irinotecan, was the
preferred first-line therapy.
Here is a more recent study from the New
England Journal of Medicine. This regimen used
IFL. This is a regimen that was shown to be
inferior in the previous study, and combined it
with Genentech's monoclonal antibody, bevacizumab,
and this study showed that IFL plus bevacizumab is
superior to IFL, and this study led to the approval
of bevacizumab for the first-line treatment of
metastatic colorectal cancer. And the label does
not say in combination with this IFL regimen; the
label says in combination with any 5-FU
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leucovorin-containing regimen.
So again, the clinician is still
struggling with what to do. The only published
data is in combination with IFL here.
And then, there is this trial by
Tournigand, a European trial, published in the
Journal of Clinical Oncology this year. This was a
randomized trial that compared FOLFIRI, an
Irinotecan-containing regimen, to FOLFOX, a regimen
that does not contain Irinotecan. Prospective
randomized trial; 113 patients per arm, and then,
second line patients crossed over to the
alternative therapy.
And what this study showed was that
basically, for first-line therapy, the two
regimens, the Irinotecan and the non-Irinotecan
regimen, were comparable from the standpoint of
response rate. Again, bringing the clinician back
to wonder what's appropriate first-line therapy?
And when one looks at survival, again, you get the
same survival no matter what you start with.
So the clinicians treating colorectal
135
cancer need all the help they can get.
Now, Oncoscreen, a German company, has
taken advantage of this dilemma and is marketing a
commercial test for UGT1A1 genotyping, and you can
go to www.oncoscreen.com, I think, and you can
read--part of it's in German, and part of it's in
English, and part of it's in misspelled
English--about the side effects of Irinotecan, also
known as CPT11, and polymorphisms in the promoter
region of UGT1A1. And it gives you the address,
and you can send blood here. I've never tried, and
I have no idea how well they're doing, but they've
taken advantage of this opportunity to actually
market the test.
And this is the data from our study, the
Innocenti study that you've heard about, shown in
greater granularity. And this was 66 patients
enrolled prospectively as you've heard. And the
study was powered around trying to show a trend, a
significant trend, 6/6, 6/7, 7/7, although the
original study design was powered to look for
diarrhea, which at the time we started the study,
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we did not understand the schedule dependent
differences in the diarrhea, and so, we ended up
looking at neutropenia as the endpoint.
As you've also heard, there are other
polymorphisms: allele 5 and allele 8. Allele 5
has been suggested to have higher glucuronidating
activity than a 6, and allele 8 has been suggested
to have lower glucuronidating activity than the 7.
And in response to the question previously asked
about ethnicity, the study was primarily caucasian,
not exclusively caucasian. I believe there were
one or two Asian patients, and there were certainly
some African-American patients in the study, but
there were certainly not enough within any
population subgroup to stratify for that.
And you see that there was a significant
trend with the 7/7s having a lower absolute
neutrophil count nadir than the other two groups,
with the 6/7 being intermediate, but clearly, the
difference between 7/7 and 6/7 is greater than the
difference between 6/7 and 6/6.
I will also add that if you want to
137
translate absolute neutrophil count nadir to grades
of neutropenia, grade three neutropenia is less
than 1,000. That's probably not clinically
significant, although it can affect subsequent
dosing. It might result in delays of treatment if
you develop grade three neutropenia.
Grade four neutropenia is an absolute
neutrophil count nadir of less than 500, and a
patient who has grade four neutropenia, who
develops a fever, is essentially automatically
admitted to a hospital and treated with parenteral
antibiotics. And so, it is very common to get
fevers when you're neutropenic, and so, that that
is a real morbidity and a real cost issue.
So others have addressed the issue of
sensitivity and specificity, and I'm just going to
again go through our data, and again, this is a
single study: 350 milligrams per meter squared
every three weeks and looking at grade four
neutropenia, the clinically significant
neutropenia, this is the extreme, less than 500.
And again, we agree with the Pfizer analysis. The
138
sensitivity is 50 percent of patients who have
grade four neutropenia who are 7/7. Specificity:
95 percent of patients who do not have grade four
neutropenia are not 7/7.
And the positive predictive value: 50
percent of patients who are 7/7 have grade four
neutropenia, and the negative predictive value, 95
percent of patients who are not 7/7 do not have
grade four neutropenia.
Now, let's put this into the context of
without testing and with testing. Without testing,
100 percent of patients are treated, and 10 percent
have grade four neutropenia. If you chose not to
treat the 7/7 patients, with testing, 90 percent of
patients are treated, and approximately 5 percent
would have grade four neutropenia. You would have
a 5 percent absolute reduction. You would test 20
to protect one.
So I put out what is my bias but I believe
is still hypothesis that pharmacogenetic testing
will improve outcomes in metastatic colorectal
cancer. That's really what we're here to discuss.
139
And I believe it will allow the clinician to select
a drug regimen based on patients' genetic, and now,
we're talking germ-line polymorphisms, genetic
characteristics, that this will lead to reduced
toxicity and potentially will lead to increased
efficacy, something that we've not previously
talked about.
My opinion is that sufficient data exist
to recommend that patients who are homozygous for
the star-28, the 7/7, should not receive Irinotecan
at standard doses. Some might say that you could
treat at standard dose and accept greater toxicity.
Some might say you could reduce the dose. I
believe that these patients would be most
appropriately treated with an alternative regimen
such as an oxaliplatin-based regimen that has the
same survival outcome as an Irinotecan-based
regimen. I cannot sit here and recommend reduced
dose, because we have no clinical data to show that
patients treated with 7/7 at a reduced dose have
comparable activity and comparable survival
outcomes to patients treated with alternative
140
regimens.
On the other hand, the optimal treatment
of patients who are at reduced risk of Irinotecan
toxicity star-one, star-one, or 6/6 is unclear.
Should they be treated with standard
Irinotecan-based regimens? Should they be treated
with high-dose Irinotecan-based regimens? There's
one European study that took patients treated with
standard dose, escalated patients who did not have
significant toxicity; they escalated them up from
350 per meter square to 500 per meter square. It's
a single-arm study, but it's got the highest single
agent response rate of any study in the literature,
and so that this may be an opportunity to reexplore
dose in a low-risk group of patients representing
50 percent of patients that are candidates for this
drug.
Or is oxaliplatin the best regimen for
these patients? We have no data to support that,
particularly for the low-risk patients.
I want to contrast this with other drugs
and other polymorphisms, because I think this is a
141
great opportunity to use pharmacogenetics to
individualize treatment of colorectal cancer. And
this is Bob Diazio's Website, www.dpdenzyme.com,
where you can learn about screening patients for
DPD enzyme deficiency. Oncoscreen also offers this
test.
What do we know about this test? And
here, you see the Oncoscreen Website, and it says
this test is supported by the German health
insurance companies. Actually, the German health
insurance companies initially--the German oncology
group initially recommended this test and then
retracted the recommendation, which is kind of
interesting. There's a history there.
And the most common mutation in DPD is an
exon 14-skipping mutation. This has an allelic
frequency of approximately 1 percent. The star-7
polymorphism has an allelic frequency of
approximately 35 percent. So there's a big
difference in allelic frequency here. DPD testing,
if you test this exon 14-skipping mutation, and
your endpoint is grade four, life threatening 5-FU
142
toxicity, without the test, all patients would get
treated, and approximately 3 percent of patients
have this toxicity. So only 3 percent of patients
have grade four toxicity from 5-FU as a single
agent.
With the test, you would treat 98 percent
of patients, and approximately 2 percent of
patients will still have toxicity, a 1 percent
absolute reduction. You would test 100 to protect
one, so much lower efficiency of this test.
And then, there's another important
polymorphism that may predict for toxicity and
efficacy of fluoroprimadines, and that's a
polymorphic repeat sequence in the thymidylate
synthase gene that has been suggested to affect
translational efficiency but not gene expression.
And this is quite polymorphic.
Here, you see the population distribution
of this 28-base pair repeat. This is data from
Howard McLeod's group. And you see that the three
repeat is more common than the two repeat, and that
there's also a four repeat present in African
143
populations.
So with parting words: oncology is widely
anticipated to be the best model for demonstrating
the clinical importance of pharmacogenetics as it
relates to germ line polymorphisms. Colorectal
cancer is an important model, because of the large
number of active agents. We have candidate genes,
candidate polymorphisms and abundant clinical data.
And I want to thank my colleagues in the
PAR group, pharmacogenetics of anticancer agents
research group. I want to thank my colleagues in
the PGRN, pharmacogenetics research network, those
sitting here today, those I've collaborated with,
and those who have had to sit through far too many
discussions of Irinotecan.
So, thank you.
DR. VENITZ: Thank you, Dr. Ratain.
Any questions or comments by the Committee
before we start our overall discussion?
Paul?
DR. WATKINS: Just a question about the
UGT1A7, which is in the gut, and we've heard that
144
diarrhea is probably a bigger issue than
neutropenia. What work has been done looking at
UGT1A1 polymorphisms and diarrhea?
DR. RATAIN: It's a very difficult
problem, because there are definitely polymorphism
1A7 that have shown to be functional that are
strongly linked to UGT1A1, because it's all one
gene. And, in fact, the linkage in UGT1A1 goes
five prime at least down to UGT1A9. So to actually
distinguish the independent effect from 1A7 from
1A1 requires a very large study.
One would not--since 1A7 is not expressed
in the liver, one would not expect it to have a
significant effect on the plasma pharmacokinetics
or on the neutropenia, but it certainly is a
candidate gene for gastrointestinal toxicity. But
we really need a lot more data, because this really
will require haplotype based analyses of the whole
UGT1 gene.
DR. SADEE: Mark, this comes back to my
earlier question about dosage escalation in
populations. You mentioned that here that in
145
patients who are apparently protected against the
cytotoxic effects, you can go to higher doses and
get higher efficiencies. So I think that really
sets an important example to pursue that.
Do you have any other examples where that
has been pursued, so rather than looking at the
negative side, one would look where you want to
avoid things. You exploit the patients that really
should get a different dose.
DR. RATAIN: Well, I mean, you know, there
have been some studies in oncology where patients
sometimes get intraindividual dose escalation, but
there's really not a large data set on that. I
mean, Dr. Pazdur may have some comments.
DR. VENITZ: Howard?
DR. MCLEOD: Mark, we heard from Dr.
Rahman's talk about how the current package insert
includes data on age and bilirubin and some other
factors that I'm forgetting, public radiation and
one other thing, as risk factors and with a need
for dose reduction.
I wonder if you could put the 7/7 genotype
146
into the context of those existing risk factors.
DR. RATAIN: Well, we've looked at age in
our data set, and we have not found at least in our
study of 66 patients a significant impact of age.
So I would say from the standpoint of neutropenia,
genotype is certainly more important than that.
Bilirubin, in our hands, is a pretty good poor
man's genotype, but this is a single institution
where the bilirubin is collected in a standard way.
Once you get into multiple laboratories, and
bilirubin is tested at various times of the day
with various degrees of fasting, you're going to
really obscure the relationship between genotype
and bilirubin.
And so, I think that yes, patients with
higher bilirubins, particularly if it's
unconjugated, are very likely to be 7/7, because
many patients within the normal range of bilirubin
are 7/7. So, but I think even there are some
subtleties. I think again, patients with very low
bilirubins probably are not 7/7, and I've used that
in my clinical practice to help determine dosing in
147
the absence of an approved test.
DR. GIACOMINI: Yes, Mark, in your study
in which you documented the neutropenia, did you
also measure pharmacokinetically the SN38, and was
it higher in those patients with the 7/7?
DR. RATAIN: Yes, we did measure SN38.
SN38 is higher in the 7/7. SN38 correlated with
neutropenia. As I said, we have some evidence that
polymorphisms in ABCC2 through our collaboration
with Deanna Krebs may relate to the
pharmacokinetics of SN38 glucuronide, which makes
it difficult to interpret SN38 to SN38 glucuronide
ratios, which we previously assumed to reflect
solely glucuronidation. It quite possibly is
determined by both glucuronidation as well as
excretion.
DR. GIACOMINI: Let me ask a followup on
the bilirubin thing. Does bilirubin actually
competitively inhibit the glucuronidation of the
SN38 to SN30 mechanistically? Is it a competitive
inhibition, so when the levels of bilirubin are
low, it's telling you two things, one, about the
148
genotype but also about just direct
competitive-competitive inhibition?
DR. RATAIN: You're asking me does
bilirubin inhibit--
DR. GIACOMINI: Yes.
DR. RATAIN: We've not looked at that. I
don't know of any data. I would not expect it to.
And there is certainly some evidence not for--it's
possible that SN38 could inhibit bilirubin
glucuronidation if the levels are pretty low, but
there are certainly examples of other drugs,
particularly the protease inhibitors, that inhibit
UGT1A1 and do competitively inhibit bilirubin
glucuronidation.
DR. GIACOMINI: Okay; but you wouldn't
expect the bilirubin and the high bilirubin levels
to be inhibiting the SN38.
DR. RATAIN: Not in--not in--I don't think
so; I mean, Dr. Watkins would have a better feel
for that.
DR. DERENDORF: I'd like to come back to
your mass balance slide. If I understood it right,
149
only about 9 percent of the parent drug gets
converted to the SN38. So what do we know about
the other metabolites?
DR. RATAIN: Would you like for me to put
that back up?
DR. DERENDORF: Yes, you can. It's the
number five.
DR. RATAIN: Messed it up; sorry.
So, this is the mass balance slide you
were referring to. And I'm sorry--
DR. DERENDORF: Only 9 percent gets
converted to the SN38, right?
DR. RATAIN: Well, 9 percent is found as
SN38, and 3 percent is found as SN38 glucuronide.
DR. DERENDORF: Oh, okay.
DR. RATAIN: And again, this is a limited
number of subjects. These subjects were not
genotyped, but approximately 12 percent, I think
it's fair to say, goes down that pathway. I think
that's a reasonable estimate. And you see 55
percent in this study was--the parent drug was
excreted unchanged. About 12 percent is oxidative
150
metabolites, metabolites known to be formed by
CYP3A, and then, we don't know the rest of this.
And again, I was not an author of this study; just
presenting it for perspective.
DR. WATKINS: Just to address that issue
of can bilirubin itself interfere with the
glucuronidation of SN38 or any other drug, in
theory, that's possible. It certainly works the
other way around. There are some drugs that will
inhibit glucuronidation in patients who have a
genetic predisposition of Jolbert's. But I'm
unaware of any studies that have looked the other
way, so I don't think I can address that.
But the question I wanted to ask myself,
one of the concerns with using genotypes of the
host as opposed to the tumor in cancer chemotherapy
is the fact that genotype and phenotype don't
always go together, particularly in an ill cancer
patient on multiple drugs with cytokines, and
certainly, if their liver is completely replaced by
tumor, genotype is irrelevant.
And one of the very unique things here is
151
this particular phase two enzyme has an endogeneous
substrate, so in effect, you have a phenotype
measurement. And my assumption up until what you
just said was that that endogeneous probe for
UGT1A1 was not very good. But what you're saying
at your institution, it's in fact very good.
DR. RATAIN: There are two studies that
address this. There's our study that within a
single institution, all patients were on a research
protocol; the bilirubins were collected at, you
know, in a fairly consistent way just by nature of
our research practice, and it looked pretty good.
There's also a study that I was a coauthor on that
relates to a Pfizer study in which a large data set
was analyzed, and bilirubin really wasn't a very
good predictor, and this was just published in the
Journal of Clinical Oncology this year by Meierhard
is the first author, and the company may want to
elaborate on that further.
DR. WATKINS: Because if I can just follow
up, I mean, the key question is what does
genotyping add to the existing tool kit of the
152
oncologist? And my assumption in all the
background reading was that it adds a significant
amount. If an alternative is just standardizing
indirect bilirubin measurements, that's another
option that could be considered, I think.
DR. RATAIN: Again, you know, from an
analytical perspective, there's a gray zone, and it
doesn't--bilirubin doesn't, you know, in a large
data set may not correlate as well as something
that is a discrete answer like a 7/7 genotype. I
think also, it might be tough to distinguish 6/6s
from the 6/7s, and I think that the 6/6s are
potentially appropriate candidates for phase four
clinical trials looking at higher doses of
Irinotecan which I think is another important
reason to find a way to get this test in the hands
of the clinical oncologists and the research
oncologists to help further explore the
dose-response of this drug.
DR. HALL: So in part to follow on from
that, then, in your hands, what would your
recommendation be for the heterozygotes? Are they
153
to be treated or given an alternative?
DR. RATAIN: I would see no reason not to
treat the heterozygotes, given the data today.
DR. MCLEOD: One of the things you
commented on was that neutropenia is an important
toxicity, and I certainly second that. And during
the discussion, hopefully, we will elaborate on
that more, because it's a common problem that is
less of a worry but probably more of a problem to
the patients.
The question I have for you is you made
the comment that you thought the 7/7 patients
maybe--might represent a data set that should get a
different drug, oxilaplatin or something like that.
But with the current state-of-the-art and the one
for probably the foreseeable future is that every
colorectal cancer patient at a decent center will
get Irinotecan. If they don't get it first line,
they will get it second line.
And so, we can't really avoid the issue
that Irinotecan is going to appear. This is a real
drug for colon cancer. And they're going to get it
154
at some point, first line, second line, third line.
So it would be worthwhile, either now get your
comments or in the discussion, trying to think
about that issue, because the drug is approved in
both these settings, and so, we do have the remit
to actually talk about it in first line, second
line, et cetera.
DR. RATAIN: Well not everybody gets it
second line. There's some patients--
DR. MCLEOD: Not everybody does, but they
should.
DR. RATAIN: What I'm saying is if--some
patients don't get to second line. If you were to
give Irinotecan first line and have a grade five, a
fatal event, they won't get to second line. So you
would say, ideally, the clinician would like to
reserve the more toxic drug for second line rather
than first line.
DR. MCLEOD: But I totally agree with your
thinking behind it. I'm just--we can't avoid it.
I mean, the patients that make it through first
line because they didn't get Irinotecan, and they
155
were 7/7, the selection now, you've just taken one
drug off the table. It's now either single agent
Irinotecan or Irinotecan and bevacizumab, whatever.
We may not be able to come up with those
things, because like you said, there is no
prospective studies. But certainly, it is an
important issue.
DR. RATAIN: You know, I think as you
think about it as a clinician, you know, if you
have a discussion with a patient, and you sit down
with them, and you talk about Irinotecan versus
oxaliplatin as first line therapy, when you talk
about Irinotecan, you have to talk about
neutropenia, diarrhea, which can be severe,
life-threatening or even fatal. And as you talk
about oxaliplatin, you have to talk about
neurotoxicity that can be persistent.
And, you know, patients have to make
choices, and I think being able to inform patients
about their relative risk, particularly of the
toxicity that scares a lot of both patients and
clinicians, which is the neutropenia/diarrhea
156
complex, I think, is useful, and I think if one
could reassure a clinician that their patient is at
relatively low risk of these toxicities of
Irinotecan, a clinician would be more interested in
prescribing Irinotecan first line.
And so, I think that this actually is
helpful, very helpful to the clinician and I think
potentially very helpful to the sponsor who is
marketing the drug.
DR. BARRETT: You mentioned the lack of
prior appreciation of the scheduled dependence on
diarrhea, and I wondered, back on your
recommendations as far as not reducing the dose,
would you feel the same with neutropenia and the
diarrhea? And I guess the followup question there
is most of this data has been summarized outside of
the time dependency, so do you feel if that kind of
information is brought to light through either dose
reduction in the context of managing toxicities
that you could perhaps devise a schedule for one
toxicity versus another?
DR. RATAIN: Well, the diarrhea is a lot
157
messier to model; no pun intended. And the
neutropenia is pretty well correlated with plasma
SN38 exposure, and we can understand that both in
the context of these studies as well as in the
context of other studies, anticancer agents and
neutropenia.
The diarrhea is not fully understood, and
we've tried to model it in the past to somehow try
to model biliary excretion of SN38, and we have one
study that actually came up with a surrogate
endpoint, or, actually, biomarker would probably be
a better term for it, which was the CPT11AUC times
the SNC38AUC over the SN38 glucuronide AUC.
But it's very complicated. I think that
the thing one is most concerned about is the
neutropenia/diarrhea complex and particularly in
the context of schedules that are more frequent
than the every three weeks, which is where you see
this problem.
DR. VENITZ: Mark, as you know, the
Committee is asked to review the evidence to see
whether we would concur with the recommendation to
158
include pharmacogenetic testing. I'd like to know
what the competition is. In other words, I'd like
to know right now what is being done to come up
with a starting dose. How do you choose a starting
dose for Irinotecan with the information right now
without genetic testing?
DR. RATAIN: Right now, people just rely
on clinical evidence, which is one size fits all
based on body surface area, even though body
surface area has been shown not to correlate with
the pharmacokinetics of this drug.
DR. VENITZ: Followup question: how do
they adjust the dose once the patient is being put
on Irinotecan?
DR. RATAIN: I think clinicians do it to
some extent by the package insert and some extent
by their personal experience.
DR. VENITZ: Okay; thanks.
Larry, I think you had the last question
and then maybe frame the questions for the
Committee so we can start the questions.
DR. LESKO: Okay; thanks.
159
Yes, Mark, and I think you may have
answered this in the last couple of minutes, but I
was looking at the relationships that Atik had
presented looking at the probability of neutropenia
and diarrhea respectively as a function of SN38
area under the curve.
They're remarkably similar, although they
were based upon mean data. So the question is is
there an indirect benefit in reducing the risk of
severe diarrhea from paying more attention to,
let's say, the neutropenic problem? In other
words, do they go together, and to what degree do
they go together?
DR. RATAIN: Yes, there's certainly an
association of the two, but they don't always go
together. But a patient with neutropenia is more
likely to have diarrhea and vice versa.
DR. VENITZ: Good. Thank you. We
appreciate your comments.
Larry, why don't you frame your questions
for us?
DR. LESKO: How about if we bring them up
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on a slide?
DR. VENITZ: That's fine.
DR. LESKO: I'll just scroll through
these.
Okay; so, as the time proceeds, I'll
scroll through the individual questions, but the
first question that we have for the committee
discussion is regarding the scientific and clinical
evidence that we're all aware of at this point. So
the question is is the evidence presented
sufficient to demonstrate that the homozygous
star-28 genotypes or 7/7s, as we call them, are at
significantly greater risk for developing a,
neutropenia, and b, the acute and delayed diarrhea
that we've heard about as an adverse event?
DR. VENITZ: And you would like for us to
vote on this?
DR. LESKO: Yes.
DR. VENITZ: So as far as the Committee is
concerned, any comments, discussion items for FDA
before we vote? And by the way, the vote is going
to be by voice vote. I'm going to call your
161
individual names, and you're going to have to tell
me whether you're a yes, no or abstain for the
individual questions as we go along.
DR. SINGPURWALLA: Jurgen?
DR. VENITZ: Nozer.
DR. SINGPURWALLA: Would you consider
removing the word significantly?
DR. LESKO: What would you suggest as an
alternative? Just--are you thinking of it because
it's a statistical--how would you convey a small
risk versus a large risk?
DR. SINGPURWALLA: Well, I'm not sure if I
could subscribe to the view that the risk is
significantly larger.
DR. LESKO: Could we use markedly greater?
Clinically important?
DR. SINGPURWALLA: I made my point.
DR. LESKO: I think the question is
intended to convey a magnitude of risk. If we want
to say clinically important, markedly, I think it's
fine. I think it conveys the same thing.
DR. SINGPURWALLA: You mean you insist on
162
an adjective?
DR. LESKO: I think a qualifier would
help.
DR. VENITZ: Any further comments?
DR. SADEE: Are we to consider these two
together, A plus B, or A separate from B?
DR. LESKO: I think we need to, based on
the way the evidence was presented today, it's
probably better to consider them separately.
DR. VENITZ: So we'll have two votes.
We'll have one on neutropenia and one on diarrhea.
DR. LESKO: Yes.
DR. VENITZ: Any other comments before I
call for the vote?
[No response.]
DR. VENITZ: Okay; then, the first
question is is there sufficient evidence of a
greater risk of developing neutropenia. And as I
said, you have three choices: yes, no or abstain.
So let me go down my list.
Dr. Barrett?
DR. BARRETT: Yes.
163
DR. VENITZ: Dr. Capparelli?
DR. CAPPARELLI: Yes.
DR. VENITZ: Dr. D'Argenio?
DR. D'ARGENIO: Yes.
DR. VENITZ: Dr. Davidian?
DR. DAVIDIAN: Yes.
DR. VENITZ: Dr. Derendorf?
DR. DERENDORF: Yes.
DR. VENITZ: Dr. Giacomini?
DR. GIACOMINI: Yes.
DR. VENITZ: That doesn't count.
DR. VENITZ: Dr. Hall?
DR. HALL: Yes.
DR. VENITZ: Dr. McLeod?
DR. MCLEOD: Yes.
DR. VENITZ: Dr. Sadee?
DR. SADEE: Yes.
DR. VENITZ: Dr. Singpurwalla?
DR. SINGPURWALLA: Yes.
DR. VENITZ: And Dr. Watkins.
DR. WATKINS: Yes.
DR. VENITZ: Okay; then, the second part
164
of that question is is there sufficient evidence to
substantiate a significantly greater risk for the
delayed diarrhea and acute delayed diarrhea? Oh,
before--I'm a yes, too. So we have unanimous.
Okay; second question, then, what about
diarrhea? Does the Committee feel there is
evidence to support significantly the increased
risk?
Dr. Barrett?
DR. BARRETT: No.
DR. VENITZ: Dr. Capparelli?
DR. CAPPARELLI: No, not yet.
DR. VENITZ: Dr. D'Argenio?
DR. D'ARGENIO: No.
DR. VENITZ: Dr. Davidian?
DR. DAVIDIAN: No.
DR. VENITZ: Dr. Derendorf?
DR. DERENDORF: No.
DR. VENITZ: Dr. Giacomini?
DR. GIACOMINI: No.
DR. VENITZ: Dr. Hall?
DR. HALL: No.
165
DR. VENITZ: Dr. McLeod?
DR. MCLEOD: No at the moment, but the
data looks like there's something there.
DR. VENITZ: That counts as a no.
Dr. Sadee?
DR. SADEE: No.
DR. VENITZ: Dr. Singpurwalla?
DR. SINGPURWALLA: I abstain.
DR. VENITZ: Dr. Watkins?
DR. WATKINS: No.
DR. VENITZ: And I would add my no, but it
does appear not only that there might be something
but it may be limited to patients that have
colorectal cancer; in other words, diarrhea may not
be present in patient populations that don't have
it.
Okay; any other comments about question
number one? So we have a unanimous vote on the
first part, and we have an almost unanimous part on
the second part of that question.
Okay; Larry, you want to present us with
the second part of this question?
166
DR. LESKO: Yes, I think on this second
question, if I can propose that the way this is
worded, it's not in a sense a votable question,
because I think we're looking for discussion; for
example, what would be the risks and benefit, what
is an appropriate study design, and it strikes me
that it doesn't lend itself to a vote. So if I can
propose that we look at this question and address
the questions that are posed on the slide in a
discussion context as opposed to a voting context,
I think that would be useful to us.
DR. VENITZ: Okay; then, I open the
discussion.
DR. GIACOMINI: Yes, one of the things I
didn't see, and I don't even know who I'm
addressing this to, this question to, but did we
ever see any data and, like, Kaplan-Meyer curves?
I don't even know if--Kaplan-Meyer curves, where
they've factored, you know, where they've looked at
survival data over time and then genotypes, put
them in categories, like the people with the star-7
genotype or the star-28 genotype are they having a
167
better survival or worse survival?
Can I ask Mark, or is he not allowed to
talk? Can I ask this to Mark? He can't talk?
DR. VENITZ: Yes, you may.
DR. GIACOMINI: Mark, I mean, just to get
an idea of the benefit to--
DR. RATAIN: There are no published data.
Dr. McLeod has a data set that may provide some
insight into the answer to your question.
DR. GIACOMINI: Oh; Howard? I guess what
I'm trying to do is get a feel--
DR. MCLEOD: Yes, there are no published
data on colorectal. There are two studies included
in the papers from--provided by Pfizer that looked
at the UGT1A1*28 genotype and survival. They were
both in the context of non-small lung cancer, if I
recall correctly. And one of the studies found
that the 7/7 genotype group from the star-28
homozygotes had a poorer survival. The other study
didn't separate the groups quite the same way, but
the group that contained the 7/7 genotypes had an
improved survival.
168
Now, neither of them met statistical
significance. They were all 0.06, 0.07 type
things; small studies, no covariance; I mean, a lot
of different issues. So my interpretation is we
really don't know the effect of UGT1A1 on survival.
In the context of colorectal cancer, there
is sufficient data, in my mind, to show that any
one study is not really going to have the full
answer on patient survival. So if you look at
patient survival for the impact of first-line
therapy is confounded by the presence of good
second-line therapy, good third-line therapy, et
cetera. And the Chornagon study demonstrated that.
Didn't matter what you gave first from what Mark
showed. If you gave the other one second, then, it
was a wash in the end.
And so, in the context of response, there
is some data that UGT1A1 may have an influence on
response, although the numbers were small and not
definitive. But there was no impact on time to
progression or survival, and so, it's inferior
data. It's as good as we have at the moment.
169
There are large studies in the cooperative groups
that are going to be able to address this in a much
more aggressive fashion because of sample size.
So I don't really know the answer. It
appears there may be an influence on response, but
there certainly does not appear to be an influence
on time to disease progression, so time until the
tumor grows again, or survival influence.
DR. VENITZ: Jeff?
DR. BARRETT: In thinking about dosing
this agent, I'm struck with Dr. Pazdur's original
comments when he talked about the fragility of the
original dose selection of this compound and the
modest response rate. So while I think most of the
discussion is focused on managing toxicities, the
loss of efficacy looms very high with this
compound. But I guess the other curious thing I
had in my mind is do we have any of the historical
data in which dose reductions were, in fact,
monitored where you could look at the
responsiveness of these markers or responses as far
as diarrhea and neutropenia go relative to a dose
170
reduction, so you can get some sense of, you know,
how, in fact, responsive those toxicities are to
dose reduction?
DR. MCLEOD: So that would be dose
reduction regardless of the cause?
DR. VENITZ: Atik?
DR. RAHMAN: I'd just like to comment on
something that we have in the package insert
already. We have data on 100 milligram per meter
square weekly dose, 125 milligram per meter square
weekly dose, and 150 milligrams per meter square
weekly dose, and what we have seen is that there is
not a whole lot of differences in the response
rates, although numbers are very small, so you
cannot do a cross-study comparison here.
But the observation that we have from the
package, and also, it is in the package insert is
that the survival, median survival across those
dosage groups is not a whole lot different so is
not the response rates.
DR. PAZDUR: The additional point is that
we do not know the relationship between response
171
rate as a surrogate for survival in this situation.
I would like to point out that this drug had in the
5-FU refractory disease population a 15 percent
response rate, yet it was able to show an overall
survival advantage compared to best supportive care
in two trials, which indicates to me that perhaps
disease stabilization or some influence on time to
progression is far more important than simply tumor
reduction size.
DR. VENITZ: Dr. Williams?
DR. WILLIAMS: I think one of the most
important questions to answer is what you're going
to base your dose selection on for the 7/7s. Mark
suggested, you know, not treating them as one
option, but obviously, you are going to have to
treat them. You cannot base it on a survival
observation. You just don't have enough patients
to make that observation.
So you're going to have to decide what to
select a dose on, and your new study, perhaps,
that's going to be done to look at dosing in that
population. So what are you going to base it on?
172
I was sort of interested with Mark, would you base
it on a targeted dose of AUC of SN38? That's a
little unsettling, because the slide that Atik
showed suggested that even with the same AUC, these
patients had a higher degree of myelosuppression.
You know, they were having grade four neutropenia
all along the bottom of that graph up and down the
AUC spectrum, so that's a little mysterious, and
then, you ask, well how about from the
pharmacodynamic standpoint for the tumor? Is the
tumor equally sensitive to the same AUC of SN38?
So, I mean, I think you're going to have
to target something. You can't, you know, you just
can't look retrospectively at toxicity, and I'd be
interested in what the Committee thinks when you do
this new study to try to individualize dosing for
these patients, what are you going to target?
DR. RAHMAN: I'd like to make a comment
about the starting dose. What I have shown in my
presentation that there is already a nice algorithm
for a starting dose for standard therapy and
continuous therapy and dose modification based on
173
toxicities in the package insert. And as I have
mentioned that we have some predictive factors
already in the package insert which are bilirubin
levels, prior radiation therapy, performance
status. Those are already indicating, recommending
a dose level lower than the standard dose as a
starting dose.
And then, if the patients do not have any
complication with that, the package insert allows
to go up to the standard dose and then move on with
that. So here is the starting dose that we can be
thinking about that can we do anything different
for the UGT1A1 patient, 7/7 patient, I mean?
DR. MCLEOD: And to follow up on that, I
wonder if maybe Dr. Morrison or one of the Pfizer
team could comment on whether dose reduction is a
covariant in terms of outcome, time to progression,
whatever your favorite is, coming back to try to
get at Jeff's initial question.
MR. MORRISON: Maybe if I could defer to
Pat to comment on that, because this was actually
before my time.
174
DR. MCLEOD: Lucky Pat.
DR. MCGOVREN: Yes, I don't have an
answer. It has not been modeled. So I don't
know--I think that the various risk factors were
arrived at very empirically, and dose reduction was
not done in any systematic way.
DR. MCLEOD: Well, Atik clearly and
correctly mentions that there is a range of doses
that seem to be equal. Those patients may have
declared themselves as being different not only in
their sensitivity to the drug but also for other
factors, and so we can't say that just because we
can start low, that means that people who are
sensitive will still do well.
DR. PAZDUR: But there is an inherent bias
in looking at the data that patients that may get
the dose reduction are poor performance status or
other issues that lend themselves to poor either
responses or poor survival outcomes. I think it's
clear, though, you know, having worked with this
drug before I came to the agency and have had a
long history, I think it would be fair to say that
175
we do not have a really good handle on what is the
dose in its relationship to the eventual outcome.
You know, could we have achieved a similar
outcome with a reduced dose? Remember, this drug
was developed in a time when oncology had the
mantra more is better, more is better, more is
better, and we kind of were hitting toward what is
the absolute highest dose that we could deliver,
and this is common in many of the oncology drugs
that we have developed over the past decade, and
now, we're trying to step back and ask this
question, which is very difficult to do.
You know, should we look at, for example,
at these patients that have this genetic mutation
to do just simply a phase one study, as we
suggested, sometimes through the company to take a
look at what would be the appropriate dose,
starting out at an artificially dose reduction and
seeing actually what the dose, because we really
don't have a good handle, even in the general
population, of what is a dose response for this
drug. And we're basing it on toxicity, basically,
176
and that's--we have to be realistic on the
development of this drug. That's how it happened
over the past decade.
DR. VENITZ: Let me make a--
DR. MCGOVREN: Yes, go ahead.
DR. VENITZ: --followup comment that gets
to item number B. I think right now, the concern
is that if you reduce the dose, we might compromise
efficacy. Well, but can you not turn that argument
around? If you improve tolerability and compliance
on a long-term treatment, don't delay treatment as
a result of a lower dose, you might actually
improve efficacy, not just compromise it. So to
me, I don't know which way to go. As you pointed
out, this drug was developed under the paradigm of
an MTD.
So by actually backing off of the dose,
you might get improved efficacy just by keeping
more patients on drug.
DR. MCGOVREN: Yes, none of the trials, I
don't think, were large enough to actually dissect
out the efficacy in patients who started at the
177
standard dose and continued on the standard dose
until their tumor progressed versus patients who
started with the standard dose, were dose-reduced
because of toxicity and then continued on a reduced
dose versus those who started on a reduced dose
because they had a risk factor at the time they
went on treatment, performance status or whatever,
and then continued on that reduced dose or even had
that dose reduced because they couldn't take the -1
level dose.
So it's just very difficult to tease out
of the available trials all of these factors which,
of course, complicates how do you design to
determine the appropriate dose for the 7/7s?
DR. VENITZ: Then maybe let me focus the
Committee on the third part of this question: what
would be needed, what would need to be done in
order to figure out what to do with those patients
in terms of coming up with a starting dose for
patients that are 7/7 genotypes?
DR. SINGPURWALLA: Jurgen? As an outsider
looking at this, the question is what is an
178
appropriate study.
Now, I can't answer that question as to
what is an appropriate study, but one thought goes
through my mind: electrical engineers use control
theory to control the movement of something or to
control the behavior of something. Has any thought
been given to using a similar kind of a paradigm in
this particular business? You start with a certain
dose; you make a prediction as to what the effect
of the dose will be; then, you observe the actual
outcome and make a correction subsequent to that
and keep on doing it in some kind of a filtering
scheme.
That is a suggestion that I would like to
put forward.
DR. MCLEOD: There are study designs that
have used a variation on that theme, both in terms
of trying to reduce the number of patients required
to study in early evaluation and also try to make
them more rapid. They've had variable success, and
in the end, we've kind of fallen back to the status
quo. But people are certainly aware of sort of
179
iterative-type processes. We just haven't figured
out how to do them very well.
DR. SINGPURWALLA: Well, I'm surprised
that you've said you've fallen back, because
control theory is one of the most successful
applications of process control, which is really a
part of this, and I'm surprised why the study
failed or why they regressed.
DR. MCLEOD: Well, it's a very successful
theory in many industries. Biomedicine is not one
of the areas where it has been a blazing success.
And so, I think with the greater understanding of
systems biology, it will be successful.
Currently, the endpoints that we talk
about in phase one are incredibly crude, and crude
endpoints don't lend themselves to intricate
approaches such as what you described.
DR. SINGPURWALLA: Are these studies
published? Is there any way I can read up on them?
DR. MCLEOD: Certainly.
DR. WILLIAMS: Let me sort of restate my
question earlier. I think from a practical
180
standpoint, certainly, you could do a phase one
study in these patients, right? And I think the
question would be that's probably what you should
do, right? Do a phase one study in the 7/7s; you
find a reasonable toxicity.
But then, what are you going to use to
provide yourself with the assurance you're in the
right place? Will it be that you have the AUC that
everybody else had with SN38? Would that provide
you assurance, or would there be some other route?
So I guess I'm just throwing out the possibility
that you would do a normal type phase one study
looking at toxicity and pharmacokinetics.
But then, what would you do, you know, to
assure yourself that you're where you want to be?
DR. VENITZ: Marie?
DR. DAVIDIAN: I just wanted to bring up,
related to that, there's been some recent work in
the statistical literature by Peter Fall, who is at
M.D. Anderson, and I was just wondering if any of
his work would be relevant in looking at toxicity
and efficacy jointly?
181
DR. WILLIAMS: I mean, I wonder, you know,
in this setting, do you think that--I guess the
only thing you could look at would be response rate
in that kind of setting. I don't know--we have to
talk to the statisticians, whether you could really
study enough patients to do that.
DR. DAVIDIAN: I agree.
DR. VENITZ: Just a followup to your, I
guess, subquestion here. I think that's the only
way you can approach it with what we know right
now. Doing a phase one dose escalation study and
see what area do you accomplish? What's the
corresponding dose?
DR. PAZDUR: But we really don't have a
good pharmacodynamic relationship between any
parameter and efficacy, either if one tries to look
at response rate or any other clinical endpoint
with this drug, and we have to be realistic about
that. And I think also, it depends on what type of
dose reduction that we're talking about with these
7/7 patients. If we're talking about a 75 percent
dose reduction, that could be quite problematic.
182
If all we're talking about is a 25 percent
dose reduction, I would feel a little more
comfortable.
DR. WILLIAMS: Let me push back to my boss
here. But what if it was a 25 percent dose
reduction, and you had the same AUC? Would that
help you? That's what I'm sort of trying to get
at.
DR. PAZDUR: Yes, but we don't know as far
as that would involve some comparison here, but we
don't know, basically, that AUC correlates with
response rate or doesn't.
DR. MCLEOD: And Atik's data says that AUC
is not AUC in terms of risk of neutropenia.
DR. WILLIAMS: For these patients, anyway,
right? There somehow seems to be a little bit of a
difference in these particular patients'
sensitivity to AUC than the other patients. That's
what I took away from this graph.
DR. PAZDUR: But, Grant, I think that
would give you a degree of some comfort here to
have some parameter that you're achieving.
183
DR. VENITZ: Final words, Larry?
DR. LESKO: If we're thinking of dosing
adjustments, whether it's a drug in oncology or
not, we generally try to bring a quantitative
analysis to the probability of an adverse event
based on exposure, whether it's a renally-impaired
patient or whether it's a drug interaction, and
depending on the outcome of that analyses, we would
reduce the dose to achieve similar area under
curve. This is pretty much how labels are derived
in terms of dosing adjustments for specific
populations.
So that concept isn't all that foreign.
It's actually the first principles of the way that
drugs work. So I think in any study that would be
conducted, the area under curve of the species that
has been shown to correlate with neutropenia to
date, which is the SN38 area under curve, would be
extremely important to measure and then use as a
guide along with other measures to determine what
the appropriate dose would be.;
I also think you don't necessarily need a
184
prospective study. There are many studies
discussed today, and not knowing the details of all
of them, one could imagine that a study would be
conducted in which efficacy or safety would guide
the treatment and then having some genotype
information in a retrospective fashion to associate
the dose that was given and the appropriate outcome
that was previously decided upon would be an
extremely powerful correlation to have, coupled
with area under curve to figure out what the right
dose reduction ought to be.
MR. BELLO: Hello. My name is Akintunde
Bello. I work for Pfizer clinical sciences. We
just thought it's interesting and important to
point out that there is actually a study that's
going to be starting shortly that's actually
looking at different doses and will be looking at
genotyping as well as exposure, PK exposure for
various moieties related to CPT11. So this is work
that's ongoing. There's a study that's forthcoming
and may give us the answers that we're looking for.
DR. VENITZ: Howard?
185
DR. MCLEOD: In the context of the
cooperative groups, this issue has also come up,
not just so much from a regulatory standpoint but
from a clinical trial standpoint, and I'm wondering
whether Dr. Ratain would be able at this point to
comment on some of the discussion that's going on
in the context of these patient genotypes. It may
be too early for that, Mark, but if you want to
comment, here's an invitation.
DR. VENITZ: Are you willing, Mark?
DR. MCLEOD: And if I put you on the spot,
I'll buy you a beer.
DR. RATAIN: Thank you.
Yes, the CLGB has a study in
development--CLGB is Cancer and Leukemia Group
B--in which patients will be genotyped; patients
with 6/6 genotype will be enrolled in a trial to
establish the safety or potential safety of higher
doses, as high as 500 milligrams per meter squared,
based on the evidence from this European trial that
some patients can tolerate 500 milligrams per meter
squared, and the hypothesis that these are 6/6
186
patients.
And if, indeed, we can establish that, the
next step would be a prospective randomized trial
in the 6/6 genotype patients of 500 versus the
standard 350.
I also, since I'm up here, I thought I
would follow up on some of the previous comments
about the pharmacodynamics of the activity. I
don't think we know what correlates with activity.
I think there is a fair amount of evidence that
it's not the SN38 AUC, and in fact, in a study that
we've completed and is in press in Clinical
Pharmacology and Therapeutics, we have modulated
the pharmacokinetics of Irinotecan with cyclosporin
A as an inhibitor of transport and also inhibits
CYP3A as well as phenobarbital is an inducer of
glucuronidation, and activity is preserved in some
patients despite very, very low SN38 AUCs.
So I would not recommend that one titrates
dosing to--from an efficacy perspective to
particular SN38 AUC. I think that is useful to
guide neutropenia considerations but not from the
187
standpoint of efficacy.
DR. VENITZ: Okay; Larry, you want to move
along to the next--
DR. LESKO: Yes, I'll just say the next
two questions are obviously up there, and the first
is not, I don't believe, a voting question, but
nevertheless, it would be useful, again, to have
some discussion of a context. Some of this has
been covered already, I think, in the prior
discussions, but if there's any other remaining
comments on the question number three in terms of
how a genotype could be complementary to
preexisting information on risk and how it might be
integrated into predelivery of the drug or
simultaneous delivery of the drug would be
beneficial.
Question four refers to some of the terms
we had about performance and probability content
information of a test, and one of the things that
hasn't been discussed is the relative value of the
expressions of a performance of a genomic test to
clinicians in terms of understanding. We've heard
188
sensitivity, specificity, predictive value, odds
ratio. There is one other, and that is the
likelihood ratio, all of which are used in the
literature to different degrees for these tests as
screening tests, basically, and any discussion or
comment people have on the relative value of these
different tests in conveying the probabilistic
nature of these genomic tests would be useful.
DR. VENITZ: Okay; then, I start with any
comments to question number three. How would you
incorporate PG information?
DR. WATKINS: Well, the point I made
before is that this is, to my knowledge, a unique
situation where you've got a
xenobiotic--polymorphic, xenobiotic metabolizing
enzyme that has an endogeneous substrate. So one
of the biggest concerns in using host genotypic
information to predict dose, particularly to
escalate dose in the 6/6 individuals is that in
fact, there might be a nongenetic factor or
additional polymorphisms that would make that
person susceptible.
189
But in this case, you have an endogeneous
marker. You've got indirect bilirubin, which is a
safety valve. So if you're missing environmental
reasons or other snips, the bilirubin should go up,
with the caveat that in total liver failure, serum
bilirubin only rises about a milligram and a half
per deciliter per day, so this would not be a
sensitive measure of acute changes.
So, apropos question number three, I think
the main unique situation here is there is an
endogenous, built-in marker for the rare
individual, or it doesn't matter how rare, the
individual that would be 6/6 genotype but in fact
would have low activity.
DR. VENITZ: Any other comments to
question number three?
DR. MCLEOD: Just to follow up on that,
Paul, I mean, it should be a surrogate marker,
biomarker, bilirubin, but, I mean, from some of the
data that was presented and some of the discussion,
it doesn't seem to be a good biomarker. I mean,
genotypes seem to offer something beyond the
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current approaches. And I know there are
approaches out there where you give a single dose
of rifampin and then six hours later take a
bilirubin level, look at induction or induction but
the increase in glucuronidation. And there's other
tests like that.
But in terms of something that could be
used in clinical practice, baseline bilirubin in
the context of multiple centers, from what Mark
described in his JCO paper, wasn't a good marker.
But yet, genotype wouldn't be influenced by those
things. So genotype wouldn't be the answer, but it
seems like an achievable answer.
DR. WATKINS: No, and I think the overall
data is that bilirubin is not as good a marker as
genotyping in this case. That wasn't the point I
was making this time, which was the comforting
thing is there's a built-in marker for someone
who's very deficient in UGT1A1 but genotypes as
having normal activity. So there's a built-in
safety valve, which is really unique, to my
knowledge, to this situation, which is very
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reassuring and, I think, makes it easier to go
ahead and push genotyping, knowing that there's a
safety factor involved.
That wasn't implying bilirubin is better;
it's just a safety valve here.
DR. VENITZ: Steve?
DR. HALL: I think one of the features of
the UGTs is they don't have a high degree of
specificity, you know. So maybe the 1A1 is a major
determinant of bilirubin conjugation, but many
others contribute a small part, and in the absence
of one, they kind of all contribute something to
the remaining activity.
So I don't think it would be surprising
that the bilirubin wouldn't work as a good index of
the enzyme, and I think the 1A family of the UGTs
is complex. They're all this single locus. They
have highly related polymorphisms that probably all
contribute in some part to the overall bilirubin
thing. So I don't think it's likely to be the
surrogate for that single enzyme defect.
DR. BARRETT: I think if the question is
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how to use this information relative to the other
factors, I mean, you have a clear idea with the
bilirubin and these other factors in conjunction
with genotype as far as the directionality goes
with Irinotecan, so as far as using it, I mean, I
think there is a practical guidance that could come
out of this, independent of the fact that it's not
a perfect correlate.
So, you know, where you are today in terms
of your understanding of this polymorphism, there
is a directionality there. Whether or not people
use it is another thing. I mean, I think the
comment from Dr. Raitan was very interesting. You
know, for the most part, there is a default to
what's in the label as far as dosing guidance, but
there's still a lot of empiricism. So the extent
to which you can provide educated information to
that empiricism, you should do it.
DR. VENITZ: Okay; then, let's move on
to--Wolfgang?
DR. SADEE: Since you bring that topic up,
I have to agree. Clearly, we have, for the star-28
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allele, we have good information that it does make
a difference. But what is missing is the
information on what is the variability within these
genotypes? And I don't think it's all that
difficult to get. In fact, while we're listening
to it, motivated to maybe look into this and maybe
provide definitive numbers as to in a population of
500 people, when you look at 1,000 alleles, how
often do you see that one is less than the other?
And what's the variability within this one
genotype?
I see this again and again with
pharmacogenetics that translate into clinical
trials, where there's a single genotype that's been
isolated; for instance, the LPR for the serotonin
transporter. And every single clinical study is
using this, and there isn't even evidence that it
does make a difference in where the gene is really
expressed.
So I think in this case, there's very good
evidence that we have a clear difference. We still
haven't defined here how much does this difference
194
really cover of what's actually happening in the
body? And so, I would like to really see that we
take the first step, and we have all agreed that
there is a correlation already with neutropenia,
but the second step must be--we must have
quantitative information: how often is this
predictive? How soft is this information? And I
think this needs to be clarified.
DR. VENITZ: Okay; then, last question,
Larry, do you want us to vote on this, question
number four?
DR. LESKO: Yes.
DR. VENITZ: Okay; so, first, let's have a
discussion on do we believe as a Committee that
current test has sufficient sensitivity and
specificity to be used. And I'm assuming response
predictor means toxic response predictor.
DR. LESKO: Yes, it does, and if there's
any discussion of the question or other measures we
haven't brought up to the Committee, that would be
appreciated as well.
DR. VENITZ: Let me start making my
195
comment first. Obviously, the numbers that we've
seen, that both Dr. Raitan and the Pfizer group has
presented, the positive predictive value looks
pretty low: 50 percent. The negative predictive
value, 83 to 90 percent, very high. So now, we
have to use my favorite concept of the utility
concept. In other words, we have to use judgment,
not just statistics.
So is a 50 percent positive predictive
value, is that something that we deem clinically
important? In other words, is that enough
assurance for a patient and/or a health care
provider to start treatment or vice versa? Is a
negative predictive value of saying I'm 90 percent
certain that with a 6/6, you're not going to
develop neutropenia, is that comforting enough?
And in my assessment, it is, based on clinical
judgment, not based on the statistics empirically
per se.
DR. PAZDUR: Could I just ask a question
before we go on? And maybe this is to Larry or
Atik: the meaning of this question, are you trying
196
to implicate in this question that all patients,
before they go on Irinotecan, should have their
status known? Is that what we're after here?
DR. LESKO: That's a different question.
I don't think that's the question we were intending
to ask. It was more directed towards if, as a
physician, I'm going to treat a patient, and I'm
going to use this test, I have to have some
information about what the test conveys in terms of
probabilities.
I think we heard about the sensitivity and
specificity, and then, we moved to predictive
values and odds ratios, so it's, for example, the
question on the likelihood ratio would be if I
tested positive, I would have a ninefold greater
chance of becoming neutropenic. That's what the
likelihood ratio would say for this. Now, what
would that mean to the clinician in terms of, a,
using the drug; monitoring the patient; using a
lower dose; making other decisions, coupled with
the knowledge of the bilirubin or other preexisting
risk factors?
197
And I think it's important not to take the
test in isolation in making these decisions but
coupled with and complementary to the other
information that would normally be at the disposal
of the patient and the physician to make a
decision. So I don't know if that answered the
question. I don't think it's asking is there a
need to prerequisite do the test before deciding to
give the drug, but it certainly would seem to be
useful, very useful a priori information.
DR. WILLIAMS: One of the points we had
discussed internally was to look at the current
label and some of the information that suggested
you might want to dose-reduce based on these
things, such as age, et cetera. And realizing
that--thinking about, I wonder what the basis of
that was?
So some things, we may have put in the
label. You might wonder about how strong the
evidence was there. I don't know if that relates
to this. It seems to a little bit.
DR. VENITZ: Howard?
198
DR. MCLEOD: My followup question, the
reason I asked Mark that question is is there
performance data for these other factors, for
bilirubin, prior pelvic radiation, performance--
DR. PAZDUR: It's very poor.
DR. MCLEOD: Okay.
DR. PAZDUR: And a lot of this has to do
with how the clinical trials were done that led to
the registration of the trials, because what we put
in the labeling usually reflects the patient
eligibility of the clinical trial that was done.
For example, age was put in the label because the
European trial restricted entry based on age.
Whether or not that would occur now, I don't know,
and we've heard from Pat that that probably doesn't
make a lot of sense, and we need to revisit this.
So the data on this are probably not as
robust as what we're seeing here, to be honest with
you.
DR. BARRETT: You're going to appreciate
you framing the question, because if I had to
answer number four the way it's written, I would
199
say no. However, if you said to me would I vote
for a test in which the negative predictive value
was greater than 90 percent as far as an aid to
dosing, I would say yes.
DR. VENITZ: Larry?
DR. LESKO: Yes, another way we tried to
think about this question is really the question
that we're trying to ask: are we trying to rule in
a risk or rule out a risk? And I think that really
reflects on the usefulness of the predictive
values. If we're trying to rule out a potential
risk with a high specificity, that would seem
valuable to know that in terms of making judgments
about the therapy with the drug as opposed to
trying to rule in someone with toxicity. It gives
an indication, but it's a little bit softer because
of those predicted values.
So I think there's a context for these
tests that have to be what is the question we're
asking?
DR. VENITZ: Well the positive predictive
value in my mind is so low because you have low
200
prevalence. It is only an average 10 to 20 percent
of neutropenia. So you have to have a very
specific, I mean, very, very sensitive test to have
a high positive predictive value.
DR. LESKO: Well, the other question is
you're exactly right: the predictive value is a
function of the prevalence, and we know that's
relatively low. Another way to think about the
question is how does it perform in the context of
other tests that are used routinely in
therapeutics, in particular in oncology, where some
of the predictive values are down around 10
percent?
Another way to ask the question is what is
the predictive value in sensitivity and specificity
if I want to detect a variant allele, namely, a 6/7
or a 7/7 patient? Now, you have a prevalence of
about 50 percent, and then, you begin to look at
predictive values; they're probably moving up on
the positive side to 85 or 90 percent at that
point, with a 50 percent prevalence.
DR. VENITZ: When you've seen Mark present
201
that it takes 20 patients tested in order to avoid
one bout of toxicity relative to TMPT, where it
takes 100 patients that need to be screened.
DR. LESKO: It was 300 to find one in the
TMPT, so this is fairly efficient.
DR. VENITZ: Any additional comments in
terms of question four before we vote?
Nozer?
DR. SINGPURWALLA: I was not sure whether
you wanted some kind of a reaction to odds ratio
versus likelihood ratio. Is that correct?
DR. LESKO: Yes, I think that would be
useful, because both are used in the field of
testing, of screening tests, and we'd like to hear
what the Committee thinks or what you think about
that.
DR. SINGPURWALLA: Well, perhaps I'm
wrong, and maybe Marie can correct me, but I
thought that the likelihood ratio is, in fact, the
odds ratio when the model is a binomial model. So
I think they are the same thing. And I was
wondering why you wanted a comment on the
202
distinction between the two.
DR. LESKO: Because I'm not a
statistician.
[Laughter.]
DR. SINGPURWALLA: Okay; so, here is my
contribution to this meeting: they are the same
thing.
[Laughter.]
DR. VENITZ: Any other comments,
statistical or not?
DR. WILLIAMS: Another comparison that
might be of interest is the design of a phase one
oncology study. We usually consider, you know, you
have one toxicity in three patients, and then,
maybe you should look at a little more; or you have
less than that, it's okay; you have more than that,
it's not.
Well, here, I think 50 percent is--of
grade four toxicity, it is kind of interesting.
That really is above what we would say is the MTD,
and so, to that extent, you might consider it's
relevant. You're getting a patient population here
203
saying is above the MTD. So from that extent, you
might consider it relevant.
DR. VENITZ: Okay; any other comments
before we call for the vote?
[No response.]
DR. VENITZ: Okay; so, we are voting on
question number four. The only friendly amendment,
predictor means toxic response predictor, right?
Because we're not talking about efficacy.
Okay; so, you have three choices: yes,
no, or abstain, and I'm going to call your name.
Dr. Barrett.
DR. BARRETT: Yes.
DR. VENITZ: That's a yes but, right?
DR. BARRETT: Yes but.
DR. VENITZ: Okay; Dr. Capparelli?
DR. CAPPARELLI: Yes.
DR. VENITZ: Dr. D'Argenio?
DR. D'ARGENIO: Yes.
DR. VENITZ: Dr. Davidian?
DR. DAVIDIAN: Abstain.
DR. VENITZ: Abstain?
204
Dr. Derendorf?
DR. DERENDORF: Yes.
DR. VENITZ: Dr. Giacomini?
DR. GIACOMINI: Yes.
DR. VENITZ: Dr. Hall?
DR. HALL: Yes.
DR. VENITZ: Dr. McLeod?
DR. MCLEOD: Yes.
DR. VENITZ: Dr. Sadee?
DR. SADEE: Yes.
DR. VENITZ: Dr. Singpurwalla?
DR. SINGPURWALLA: I'm afraid I have to
abstain.
DR. VENITZ: The statisticians abstain.
DR. SINGPURWALLA: Well, I'll make a
comment that if somebody starts with a yes, there
is a high probability that the yeses will--
[Laughter.]
DR. VENITZ: Okay; Dr. Watkins?
DR. WATKINS: I'm going to abstain. I
mean, we've all agreed that the test predicts
neutropenia, but this is somewhere between that
205
answer and do we think all oncologists should be
doing it, and I'm just not sure where the question
really is in that spectrum, so I'm abstaining.
DR. VENITZ: Okay; so I'm going to vote
yes, so we have three abstentions and nine yes, for
a total of 12.
And I think that does conclude our morning
session, so I appreciate you all's contribution.
We'll take a break until 1:00 for the open
public hearing, and the Committee members have a
room for lunch reserved in the restaurant right
here in the hotel, Martindale's.
[Whereupon, at 12:12 p.m., the meeting
recessed for lunch, to reconvene at 1:00 p.m.]
- - -
206
A F T E R N O O N S E S S I O N
[1:08 p.m.]
DR. VENITZ: Our next agenda item is the
open hearing, and we do have one letter submitted
by Dr. Rowling, a member of the Committee who was,
unfortunately, not able to attend. She submitted a
letter for your information that is attached to
your packages and will be posted on the Website.
Other than that, we have nobody here for
public hearing.
Then, our next order of business is
conflict of interest statement.
Hilda?
MS. SCHAREN: Hello.
The following announcement addresses the
issue of conflict of interest with respect to this
meeting and is made a part of the record to
preclude even the appearance of such.
Based on the agenda, it has been
determined that the topics of today's meeting are
issues of broad applicability, and there are no
products being approved. Unlike issues before a
207
subcommittee in which a particular product is
discussed, issues of broader applicability involve
many industrial sponsors and academic institutions.
All special Government employees have been screened
for their financial interest as they may apply to
the general topics at hand.
To determine if any conflict of interest
existed, the agency has reviewed the agenda and all
relevant financial interests reported by the
meeting participants. The Food and Drug
Administration has granted general matter waivers
to the special Government employees participating
in this meeting who require a waiver under Title
18, United States Code, Section 208. A copy of the
waiver statements may be obtained by submitting a
written request to the agency's Freedom of
Information Office, Room 12A30 of the Parklawn
Building.
Because general topics impact so many
entities, it is not practical to recite all
potential conflicts of interest as they apply to
each member, consultant and guest speaker. FDA
208
acknowledges that there may be potential conflicts
of interest, but because of the general nature of
the discussions before the subcommittee, these
potential conflicts are mitigated.
With respect to FDA's invited industry
representative, we would like to disclose that Dr.
Paul Fachler and Dr. Gerald Migliaccio are
participating in this meeting as nonvoting industry
representatives acting on behalf of regulated
industry. Dr. Fachler's and Mr. Migliaccio's role
at this meeting is to represent industry interests
in general and not any one particular company.
Dr. Fachler is employed by Teva
Pharmaceuticals USA, and Mr. Migliaccio is employed
by Pfizer. In the event that the discussions
involve any other products or firms not already on
the agenda for which FDA participants have a
financial interest, the participant's involvement
and their exclusion will be noted for the record.
With respect to all of the participants,
we ask in the interest of fairness that they
address any current or previous financial
209
involvement with any firm whose product they may
wish to comment upon.
Thank you.
DR. VENITZ: Thank you, Hilda.
The second topic of today's meeting is in
regards of drug-drug interaction and will be
introduced by Dr. Shiew-Mei Huang, who is the
deputy director for sciences of the Office of
Clinical Pharmacology and Biopharmaceutics.
DR. HUANG: Thank you, Jurgen.
Good afternoon. Before I talk about
relevant principles of drug interaction concept
paper that is published as part of the background
information for this Committee's discussion, I'd
like to briefly summarize some of the publication
and discussion that happened to lead to a revision
of this guidance.
Back in 1997 and 1999, we in CDER, with
CBER, published two guidance documents for
industry: the 1997 on in vitro drug interactions
and 1999 on in vivo drug interactions, focusing on
study design, data analysis, and recommendations
210
for labeling. Subsequent to the publication of
these two guidance documents, we had various public
workshops discussing different topics related to
drug interactions.
We also had a lot of internal discussions,
including CDER-wide scientific round discussions.
There is one example of publication on one of the
public workshop, and you have heard from Dr. Lesko.
We have various internal documents. Some of them
are published, such as the good review practices,
where we have included important drug interaction
questions to ask during the review of the
applications. And we also have drafted a MAP,
which is Manual for Policy Procedures about
cross-labeling and also about in vitro evaluation
of drug interactions.
PhRMA has published a white paper last
year on general drug interaction issues, and as Dr.
Lesko summarized earlier this morning that this
advisory group, the Advisory Committee for
Pharmaceutical Sciences and the Clinical
Pharmacology Subcommittee, at a meeting last year
211
in April, we discussed the proposal of classifying
CYP3A inhibitors, and we also touched upon PGP
inhibition-based interactions, and in November, we
talked about some of the emerging important
enzymes, such as CYP2B6 and 2CA and their role in
the evaluation of drug interactions.
So based on these discussions, the CDER
working group with the contribution from CBER, we
have drafted an interaction guidance, which is in
internal review right now. And this will be
published soon as a draft for comments, and when
the guidance is finalized, this will replace the
two in vitro and in vivo guidance documents
currently posted on the Internet, where we have
updated information and recommendations on drug
interaction evaluation.
We also have this guidance to address some
of the recent labeling rule change. In 2000, we
had published a proposed rule about professional
labeling of prescription drugs. The final rule
will be published soon, with accompanying various
guidance documents to talk about various segments
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of the labeling.
So I'd like to talk about some of the
principles that we discussed and the drug
interaction concept paper which was released for
discussion purposes only.
In this concept paper, we stress the
importance that metabolism and drug interaction
information to benefit-risk assessment for new
molecular entities prior to market approval. We
have learned our lessons from recent U.S. market
withdrawal from 1998 to 2003. Note that this table
was constructed prior to the withdrawal of Vioxx,
so we did not include Vioxx in the table.
However, if you look at these 10 drugs
that were withdrawn between 1998 and 2001, where
they had been approved between 1985 and 1999, these
10 drugs with different characteristics and use;
there are some antihistamine or cholesterol
lowering. But if you look at these, the risks,
five of the 10 drugs, the risk of drug interaction
has contributed to withdrawal. And out of these
five drugs, if we look at Terfenadine, Astemizole,
213
Cisapride, Cerivastatin, these are substrates of
cytokine p450 enzymes or other enzymes or
transporters, while Mibefradil is an inhibitor of
CYP enzymes, PGP and possibly other transporters.
So these examples demonstrate that it is
important to evaluate other drugs' effect on the
new molecular entity and the new molecular entity's
effect on other drugs. We have a recent example
where a new molecular entity is a CYP3A inducer,
and the risk of drug interaction has contributed to
that drug's nonapproval. So again, we want to
stress it's important to evaluate inhibition-based
interaction as well as induction-based interaction.
Second principle I'd like to talk about in
the concept paper is to talk about an integrated
approach to evaluate drug interaction in vitro, in
vivo, specific and population pharmacokinetic
studies where when you look at the totality of data
to estimate the potential for drug interaction, and
this, hopefully, will reduce the number of
unnecessary studies and to optimize our knowledge.
In the concept paper, we discuss that for
214
the evaluation of metabolic interactions, as far as
evaluating the new molecular entity as an
inhibitor, we said it's important to study the five
major CYP enzymes: 1A2, 2C9, 2C19, 3A and 2D6. As
far as evaluating as an inducer, since the 2D6 has
not been shown to be inducible, here, we're
stressing the importance to study the other four
major CYP enzymes.
We know it's important to study other
drugs' effect on the new molecular entity, so it's
important to evaluate the metabolic profile of the
new molecular entity. We think it's important to
evaluate those five CYP enzymes, but when none of
these enzymes are found to be responsible for the
metabolism, it may be important to evaluate other
CYP enzymes such as CYP2B6, 2C8, rarely 2E1 or
other phase two metabolizing enzymes.
This morning, we have discussed how the
genetic variation would affect a drug with a
substrate for UGT1A1. Unless we know this drug is
metabolized by UGT, we probably won't know how the
genetic component would affect its metabolism and
215
its clinical response.
As far as inhibition, we have included an
appendix to talk about how to evaluate in vitro,
and we have indicated one parameter to look at
possibility of in vivo inhibition based on in vitro
data is to look at the I over KI, I as the
concentration of an inhibitor, which we like to use
a CMAX at a steady state at a highest dose and
compare to a KI of get a five major CYP enzymes.
The PhRMA paper indicated I over KI of 1
or 0.1. More than 1 is likely to be an inhibitor.
We did not specifically indicate what ratios,
although we did mention when the I and the KI were
separated by a very large--such as 50, then, it's
not likely to have an interaction. However, we
also indicated that we could rank order the in
vitro data to determine and prioritize the in vivo
studies.
For example, this is one new molecular
entity. And here, the five major CYPs are
evaluated. We like to look at the KI value.
Sometimes, we don't have the KI values, because
216
when you have very high concentration, you still
don't see inhibition. Sometimes, IC50 will be
expressed as higher than the concentration being
evaluated. So in this case, if you look at I and
KI, you would say, well, this is a very likely
event, and this one falls into probable, and this
may not be likely.
In order for us to--we don't have a
definite number to work with, I over KI ratios, so
the suggestion would be to look at the KI in rank
order, and you probably want to evaluate the CYP
that's most potently inhibited first in vivo. If
the results are negative, then, you wouldn't have
to evaluate the other that's less potently
inhibited, but if the results are positive, we
couldn't extrapolate, and we need to evaluate the
other CYP enzymes.
As far as induction, we have a new message
in the concept paper. We say that induction can be
addressed with in vitro methodology. In our
previous guidance documents, we mention that
induction can only be evaluated in vivo as a
217
technology for evaluation has not--there's
insufficient data to support a use of in vitro. So
we said we would look at the induction data based
on in vivo at this point.
I have mentioned earlier, it is important
to evaluate CYP1A2, 2C9, 2C19 and 3A. However, we
are suggesting that the initial in vitro evaluation
can be done with 1A2 and 3A. Part of the reason we
thought the 3A could be coinduced with 2C9 and
2C19, so if the results from CYP3A is negative,
then, you don't have to evaluate 2C9 and 2C19. Dr.
LeCluyse is going to show us some data to support
that argument later.
Again, we say negative results may
preclude in vivo evaluation of the other important
CYPs that we have mentioned that are important to
evaluate in a submission. Unlike the inhibition
study where we only say a positive control is
optional, for induction, we say a positive control
is recommended. For example, if you're evaluating
CYP3A, we think it's important--we could use
revamping as a positive control.
218
We think it's very important, since our
recommendation is if the data is negative, then,
you don't have to do in vivo. If it's positive,
then, you need to do an in vivo study. So it's
important how we define when it's positive. The
original concept paper, we said we can either use a
40 percent of positive control as a cutoff or
twofold of the negative control.
With subsequent discussion that when we
look at both 3A and 1A2, there may be too much
false positive if we use the twofold negative, so
we have dropped it right now, and we are
discussing, we are asking the Committee to comment
on the appropriateness of using a 40 percent of
positive control to suggest a possible induction,
and this 40 percent number was based on the PhRMA
white paper.
Ever since we have started to discuss the
appropriateness of using in vitro induction
methodology to evaluate induction, we have received
quite a few comments. Well, then, it's now a need
to conduct in vitro inductions for all new
219
molecular entities. And our answer is no.
However, it's important to address induction. You
can either use in vitro or in vivo. It's important
to address, but you don't necessarily have to use
in vitro, but it may be a good approach to start
with in vitro. And then, if the results are
negative, then, you're done, but if it's positive,
then, you continue. This is sort of what I just
said. Positive in vitro needs to be followed with
in vivo.
And I want to mention that induction can
be part of evaluation of in vivo inhibition
studies. Oftentimes, we have seen inhibition
studies carried out with Midazolam when we're
evaluating the possibility of inhibition of CYP3A
with Midazolam. And when the sponsor conducted a
study with multiple dose, multiday evaluation, when
the results are negative, you could claim that this
is not an inhibitor. At the same time, you could
also say it's not an inducer.
Study design data analysis is key and
should be well thought out so that we can provide
220
important information for proper labeling. In our
concept paper, we said we need to design a study to
maximize seeing an effect. And we said that when
you are starting with an inhibitor, we'd like to
use the highest dose, shortest-dosing interval of
an inhibitor.
A common question is always, well, if we
are evaluating inhibitor effect using ketaconazole
to evaluate a CYP3A inhibition, should we use 400
or 200 milligrams? Many of our submissions use
multiple doses. And so, the question is really
whether what is the dose level that should be
employed.
The literature data has many studies using
400 or 200 milligrams. However, they have varied
study design. The difference in study length,
timing of coadministration or different
populations, so it's difficult to compare
intrastudy. And that's why later on, I will show a
study where we compare within study, where the
subject was given both 200 and 400 and make a
direct comparison.
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However, in one literature data, one
publication has shown that ketoconazole CMAX
concentration appeared to show a correlation with
the inhibition effect on Midazolam. If you look at
the AUC ratio where Midazolam was given with
ketoconazole versus when it's given alone, you can
see the ratio increase as ketoconazole levels
increase.
This study was conducted only with one
dose of ketoconazole, but this is the initial base
of our recommendation to sponsors that we should
use a higher dose of ketoconazole when conducting
interaction studies, however, we did include a
study to evaluate 200 versus 400 milligrams of
ketoconazole as part of a collaborative research
and development collaboration with Indiana
University, and Dr. Steve Hall is the principal
investigator for the collaboration.
And this is a preliminary result that was
shown from that study, where Midazolam, after IV
and oral were compared when it's given together
with 200 milligram dose of ketoconazole or 400
222
milligrams of ketoconazole given for six or seven
days. You can see that after IV administration,
the extent of interaction is smaller as compared to
oral. It's about fourfold after the 400 milligram
dose, and it's about threefold after the 200
milligram dose.
After oral administration, the extent of
interaction is much higher. The AUC ratio is about
15 after the 400 milligram dose; it's about tenfold
after the 200 milligram ketoconazole dose. So
based on the literature data and the study
comparison that I just showed you demonstrate that
CYP3A inhibition after ketoconazole is dose
dependent with 400 milligram dose having a higher
effect than a 200 milligram dose. And we believe
that inhibition studies with ketoconazole should be
conducted at a 400 milligram dose.
However, we have seen in many applications
that a study is already being done with 200
milligram doses. So questions always come up:
well, if you're already studying at 200 milligrams,
do you need to conduct another study with 400? And
223
there are several cases where the sponsor went back
and conducted a 400 milligram dose, and it showed a
difference. The 400 milligram produced a higher
extent of interaction.
There is also a case where a 200 milligram
dose was already demonstrated to have a very large
extent of interaction and is likely to result in a
contraindication. In that need, may not need to
have an additional study, because if you already
know what 400 milligram results will--data will
result in what kind of labeling; it's probably very
similar. It's a contraindication. So in that
case, you don't need to conduct another study. We
need to look at the results and other information
such as exposure response before we automatically
request an additional study.
What about other study design issues?
This one was not directly addressed in the concept
paper, but it was frequently asked: can we use the
cocktail approach where, in vivo, a mixture of pro
substrates for three to five of the major CYP
enzymes were given together with the new molecular
224
entity to evaluate the new molecular entity as an
inhibitor or inducer?
We say yes, they can be used if they are
properly designed; probes are specific; they do not
interact with each other, and there are a
sufficient number of subjects that are used in the
evaluation and if the results are negative, then,
we could preclude further evaluation. However,
many of these cocktail studies used a ratio such as
metabolic ratio in the urine or plasma level, and
it's difficult to extrapolate to assess what would
be the extent of interaction, unlike the studies
that we used where you look at AUC ratios, where
you know it's a fivefold increase or a tenfold
increase. In that case, then, we may need
additional evaluation to provide some quantitative
information.
And again, we have seen cases where some
of the older cocktails were used, and one of the
probes may not be specific, and it may interact
with one of the--it also affect the other CYP. The
other--the data from the other CYPs can still be
225
used, and it could be used in combination of other
in vitro-in vivo data. It could still provide
useful information. Again, we don't automatically
throw away data from a study just because it's not
well designed and certain parts of a design.
Again, the design issue, we were often
asked what kind of substrates or inhibitors or
inducers that should be used both in vivo and in
vitro? What concentrations of substrates should be
used in vitro? We've been asked so many questions,
and this happened always in a sponsor meeting. So
the working group thought it would be good if we
can provide tables in the concept paper on some of
the proven or good in vivo and in vitro probe
substrates, inhibitor inducers.
Earlier, we thought this may be too
proscriptive, and the tables may be outdated
frequently. And we thought we could address it by
using a Web link so we can provide more frequent
updates of the tables than the guidance itself.
And this is just one example of in vivo
probes that we have included in the concept paper.
226
You can see, in addition to the five major CYPs, we
also included information on 2B6, 2C8, since these
are emerging, and 2E1, and you can see that in some
of the well-defined polymorphic enzymes such as
2C9, 2C19 and 2D6, we also think that the
evaluation of pharmacokinetics in poor metabolites
of those enzymes and compare that to the extensive
metabolizer, and this could be done in lieu of a
drug interaction study.
We also indicated that for 1A2, since we
couldn't find a good inducers, since omeprazole has
not been consistently providing induction effect
based on some of the criteria that we mentioned in
our table that made these drugs onto the list, so
we provided that perhaps the pharmacokinetic
evaluation of smokers versus nonsmokers could be
conducted in lieu of an induction study.
And this, I already mentioned, that the
kinetic evaluation in poor metabolizer or smokers
can be used, and we also mentioned, we put a
statement that it may be important to evaluate
interaction based on a pathway in poor metabolizers
227
of enzymes, of the other pathway, which is
considered to be major and the extensive
metabolizer. For example, if the drug is a
substrate for both CYP2D6 and 3A, then, in poor
metabolizer, the CYP3A may be an important pathway,
and you may want to consider the evaluation of that
pathway.
In addition, based on information that we
know about herb, dietary supplement interactions,
juice, food interactions, we thought it's important
to also start to look at the protocols, and we
provided some sample language that should be
included in a clinical protocol when we evaluate
drug interaction, so that when we look at the
interaction results, they're not compromised by the
unknown factors that are contributed by these other
factors.
The concept paper not only discussed
metabolism-based drug interactions, but it also
included transporter-based drug interactions,
although right now, we focus only on PGP-based
interactions. In our concept paper, we mentioned
228
that if a new molecular entity is an inhibitor of
PGP in vitro, then, we think a clinical study using
digoxin may be appropriate. And we have discussed
this in the April meeting last year, and this was
just a summary of some of the data that are
presented at that time.
This is the digoxin plasma AUC or
steady-state concentration that's the ratio when
it's given with these drugs or without. And you
can look at some of the known inhibitors of PGP:
quinidine, retonavir, verapamil, has increased the
ratio to 1.5 to 2.5-fold. Here, grapefruit juice,
aprepitant did not show an interaction.
The known inducers of PGP, St. John's
wort, rifampin, has shown to reduce the plasma
concentration by 20 to 30 percent. And we'd like
to ask the Committee to comment on this point
again.
So we talk about the new molecular entity
as an inhibitor. What about it as a substrate?
And we thought it's important to discuss it with
the status of its CYP3A, whether it's a CYP3A
229
substrate or not. So we said in a concept paper if
a new molecular entity is a substrate for PGP and
CYP3A, and we have a lot of cases like this, then,
the clinical study with a dual inhibitor or a
multi-inhibitor may be appropriate. We just put in
ritonavir as an example, because ritonavir affects
multiple pathways, and here, we're just using
example data from vardenafil labeling, where you
see the AUC ratio of vardenafil when it's given
with these compounds as compared to when it's given
by itself.
And you can look at ritonavir, indinavir,
ketoconazole. Vardenafil is a CYP3A substrate, and
you can look at the strong CYP3A substrates have
shown a large degree of interaction. It's more
than tenfold, and here, ketoconazole is only given
as 200.
The moderate inhibitor, I will explain
about in the classification on CYP3A inhibitors
later, but erythromycin has shown a little bit
lower than fivefold increase in vardenafil.
This should show even these three
230
compounds are classified as strong 3A inhibitors,
but they did show some differential effect. And
so, there's a possibility that ritonavir, because
of its effect on other pathways, in addition to PGP
and other transporters that contributed to a much
larger effect on the substrate.
So we say if a new molecular entity is a
substrate of PGP but not a substrate of 3A, then, a
clinical study with regular known PGP inhibitor may
be appropriate. Again, it's hard to differentiate,
because some of the compounds that are listed here
are also 3A inhibitors, but they're not as strong
an inhibitor.
And here, this is the same table I have
listed earlier with digoxin, so you can see one of
these PGP inhibitors could be used when we have a
new molecular entity which is a substrate of PGP
but not 3A. So we're asking the Committee to
consider whether CYP3A status should be a key
factor when we decide what kind of inhibition study
to conduct, when the drug is a PGP substrate and
also whether we have sufficient data to recommend
231
routine evaluation of PGP interaction if a
substrate, if a drug is a substrate of PGP.
Finally, the last issues regarding study
design: we put in some statement in the concept
paper about the use of multiple inhibitors or
multiple impaired system. When we evaluate the
possibility of a serious adverse events such as we
use the QT prolongation to assess the probability
of trassar DuPont's, we have recommended in the QT
concept paper, actually, it's an ICH document right
now, to use perhaps a strong inhibitor of the major
pathway.
In addition, we have seen examples where
either the reviewer has recommended or the sponsor
has conducted that multiple inhibitors--this is
different than multi-inhibitor. It's a multiple
inhibitors to attack different pathways or, using
one inhibitor for one pathway in poor metabolizers
of the other pathway in the evaluation.
And we have examples such as
telithromycine. An inhibitor such as ketoconazole
was used in the evaluation of a QT prolongation to
232
obtain maximum exposure. We also have cases where
a strong inhibitor was used, for example, when we
evaluated vardenafil. A separate study prior to
the QT evaluation was conducted to estimate what
the maximum exposure that's attainable with a
strong inhibitor; then, use that information to
design a high dose study to evaluate QT
prolongation.
Finally, though not directly related to
this issue, we think the use of multiple inhibitors
of one pathway is also important. Particularly,
right now, we're talking about possibility of
classifying CYP3A inhibitors to moderate inhibitors
and possibly monoinhibitors. That was suggested in
the PhRMA position paper, and we have research
ongoing again with Indiana University, looking at
multiple moderate inhibitors' effect, whether they
would be additive or synergistic or producing an
effect like you're giving a strong inhibitor.
Next point I'd like to stress is this is
the same point that we have stressed in the
previous guidance in 1999, that it's important to
233
establish a therapeutic equivalency boundary for
the new molecular entity, so we will be able to
interpret the extent of interaction based on
interaction studies and what to put in the
labeling.
And here, I am going to present a
hypothetical case where we use combined data from
different applications. This new molecular entity
was given with ketoconazole, a strong 3A inhibitor.
This new molecular entity is a 3A substrate. And
you look at the CMAX increased by fourfold.
The moderate inhibitors: erythromycin,
verapamil, increased by threefold. The AUC showed
similar effect. I put CMAX here because one of the
adverse events was believed to be related to a
maximum concentration.
And we look at exposure response data,
where from the safety and efficacy database, we try
to relate the exposure to one of the endpoints for
efficacy, and one of the endpoints was adverse
events. Here, I simplified the outcome. Actually,
we have several endpoints for both efficacy and
234
safety. And based on the data, between 15 and 60,
the exposure, consider that the drug will be
efficacious and safe. However, because of
ketoconazole's effect, it's varied. It's very
large. We think it's important to advise against
abusing strong inhibitors with this drug.
For moderate inhibitors, if you approve
the dose of 15 and 30, since if you give 30
milligrams, and the moderate inhibitors will
increase the exposure to outside the safe and
effective exposure range. So we would recommend to
use a lower dose.
My final point is that labeling language
needs to be useful and needs to be consistent. In
our concept paper, where we said that if a drug has
been determined to be a sensitive substrate or a
CYP3A substrate with a narrow therapeutic range,
and I'll explain a definition later, and it does
not need to be tested with all strong or moderate
inhibitors of 3A in order to warn about it in the
labeling.
And in the concept paper, we gave
235
examples. We have many tables. And one table is,
well, strong, examples of strong 3A inhibitors or
moderate CYP3A inhibitors. Here, the strong 3A
inhibitors, we have included. The definition is
any substrate, any--if an inhibitor, if that caused
more than fivefold increase in the area under the
curve of a CYP3A substrate. And that's not limited
to Midazolam, then, we listed it as a strong
inhibitor.
The PhRMA paper specifically talks about
Midazolam. But since there are many strong CYP3A
inhibitors, we do not have Midazolam data, and we
think it's important to include these strong
inhibitors in the table, since we do have
information from the other.
The moderate inhibitors, we have similar
definition with a PhRMA white paper, except we
added some specifics. We said that a moderate
inhibitor is one that caused a more than two but
less than fivefold increase in area under the curve
of a sensitive substrate. It has to be a sensitive
substrate, and the inhibitor needs to be given at
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the highest dose and lowest, shortest dosing
interval, so that we won't misclassify a strong
inhibitor because a study was conducted with a low
dose, a long dosing interval, or it's not--it was
conducted not with a sensitive substrate, so you
may underestimate the extent of interaction and
therefore misclassify.
And one example I've already shown that
even the study was only conducted with ketoconazole
for a strong inhibitor but it does not prevent us
from labeling it with other strong inhibitors. And
for moderate inhibitors, even only done with
erythromycin and verapamil, we will be able to
label with the other additional moderate
inhibitors.
In the concept paper, we also mentioned
that if a drug has been determined to be a strong
inhibitor of 3A, it does not need to be tested with
all sensitive substrates or substrates here
specific about CYP3A with a narrow therapeutic
range. And in the concept paper, we included
examples of sensitive substrates or substrates with
237
a narrow therapeutic range.
This is a new definition. The PhRMA white
paper did not discuss a sensitive substrate in the
definition. And here, we defined that sensitive
substrates are drugs that AUC will increase
fivefold or more with an inhibitor. It doesn't
have to be a strong inhibitor; any inhibitor.
A CYP3A substrate with a narrow
therapeutic range: this would be applicable to
drugs that are not a sensitive substrate. However,
the increase in exposure because of
coadministration with a CYP3A inhibitor may result
in serious safety concerns, such as trussar DuPont,
so you can see there are quite a few drugs:
cisapride, astemizole, terfenadine; these were
removed from the market but are included in the
table just for illustration purposes.
An example of a labeling based on this
table would be--I'm using telithromycin as a case.
This drug, when, it's given with Midazolam,
increased the area under the curve by sixfold, so
in definition, it's a strong inhibitor. So in the
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labeling, we said telithromycin is a strong
inhibitor of the cytochrome p4503A, and we also
said the use of simvastatin and other statins here
concomitantly with telithromycin should be avoided.
We also said that the use of telithromycin
is contraindicated with cisapride and pimozide.
And you will notice, based in the information in
the summary of our study, we did not evaluate all
of these drugs that are listed here. For sensitive
substrates, we only evaluated with simvastatin, but
it does not prevent us from listing other sensitive
substrates.
For substrates, CYP3A substrates with
narrow therapeutic range, the pimozide was not
evaluated. But again, because of what we classify
it as a substrate with narrow therapeutic range, we
put it in our labeling. Right now, we have various
discussions on how to label strong inhibitors; what
sensitive substrates to put in the labeling when we
are evaluating one, and we may come up with a
different list. Therefore, we think it's important
that we publish the labels and constantly update it
239
so that we have consistency among the labeling of
different drugs.
So in summary, we think metabolism drug
interaction is key to benefit-risk assessment, and
I think based on today's discussion, we probably
will add some transporter information as well. An
integrated approach may reduce the number of
necessary studies and optimize our knowledge.
Study design data analysis is important and
information for proper labeling, and we have
devoted many pages of our concept paper on study
design, and we've also added an appendix on the
conditions of in vitro evaluation: what are the
study design and data analysis issues?
The thing we need to establish,
therapeutic equivalency boundaries, so we can have
proper interpretation of the clinical outcome and
put it into a useful information in the labeling,
and we have added tables of classification of CYP3A
inhibitors, substrates, to hopefully that we have
consistent and useful labeling.
And I'd like to acknowledge the drug
240
interaction working group. It consisted of many
members from our office, the Office of Clinical
Pharmacology and Biopharmaceutics; from individuals
outside our office, the Office of Pharmaceutical
Science; individuals from CBER; some of them have
joined us after the reorganization and also from
the Office of Medical Policy.
I think my time is up. Do you want to
take any clarification questions?
DR. VENITZ: Thank you.
Any comments or clarification questions
for Shiew-Mei by the Committee?
DR. JUSKO: I have one.
DR. VENITZ: Go ahead.
DR. JUSKO: Shiew-Mei, that was very clear
and impressive. With the study of the ketoconazole
interaction that you showed, I didn't see that
using 400 milligram ketoconazole was that much
better than 200, and I would have come to the same
conclusions with either dose. Why are you so firm
on 400, where there may be some additional negative
aspects as opposed to 200?
241
DR. HUANG: The example, since we use a
sensitive substrate with Midazolam, you probably
can see, well, 200 milligrams already gives you a
tenfold increase, and we probably will classify to
say not to use it together with some more sensitive
substrate already.
If the exposure response data are such
that, then, you don't need to do another study.
However, we have a lot of compounds where CYP3A is
part of the pathway. So in that case, the results
are not clear cut. We did have one example where a
threefold and fivefold difference, from these two
different doses, and it would make a difference.
For example, one of the examples that I showed you,
the moderate inhibitor and strong inhibitors, one
shows fourfold; one shows threefold, and we do have
a different proposal for labeling, because
depending on the compound's exposure response,
fourfold increase is going to take you outside that
safe and effective exposure range; then, you would
contraindicate. But if it's threefold, it may
still be within the range, and you can either using
242
a dose reduction in the labeling to address that
issue.
So for less sensitive substrates, the
difference, three to fourfold or versus one to
twofold, it will make a difference in the proposal
and the labeling.
DR. GIACOMINI: Do I have that--yes,
Shiew-Mei, that was an excellent and very clear
presentation. I just have a couple of comments
related, of course, to transporters and how we have
to begin thinking of not really metabolism but more
metabolic pathways, which would include maybe an
influx transporter, the enzyme and then an eflux
transporter, which may be all part of a pathway.
So when you've indicated here, and you've
got particularly sensitive substrates, and you have
examples of inhibitors, and many of these are
dirty; they'll inhibit different things along the
pathway, and I think it would be helpful in this
paper at some point to at least indicate what may
be a dual substrate and a dual inhibitor, and are
you planning to do that dual, triple, whatever?
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DR. HUANG: There are a lot of
publications that did suggest this, and what we
want to put in the guidance is where it's going to
be useful in the study design or in the labeling,
what's going to be translated to a clinical
setting. So any information that may not be
helpful; for example, if we say we evaluate this
drug as an MRP substrate, and we know it's both
CYP3A and MRP.
However, we really couldn't recommend to a
sponsor a certain type of study to conduct besides
a PGP. We do have some proposals; or we don't know
what to do with the data, and how would that help
prescribing a physician or health care provider's?
Then, we don't think that that will belong to the
guidance. It will belong to the literature, and we
have enough information to make a recommendation
under this case, what should you do in your study
design? Then, we will include that in the
guidance.
DR. GIACOMINI: I mean, I agree with you.
I hear what you're saying, but it seems to me like
244
if somebody has done some kind of an inhibition
study, they may make an interpretation; they're
going to use that to make some kind of an
interpretation, and you're focused mostly on the
interpretation as it relates to the dose of the
drug. But I'm just wondering about even a
mechanistic interpretation by at least indicating
that certain substances may, certain compounds may
be inhibitors of both a transporter and an enzyme,
that some caution in the--especially, you're going
to extrapolate, right? Because you're going to say
well, now, that we showed this, you better be
careful for all of these, all of these compounds,
which may also be substrates of CYP3A4 when, in
fact, the transporter was the bigger part of the
interaction, and that wasn't--
DR. HUANG: Yes, well, I would welcome the
Committee's discussion, because I did have some
question to see what other transporter that should
be evaluated. But you will notice, even we put all
the tables, when we want to translate one study to
the others and put in the labeling, we only provide
245
some very specific information. For example, we
say ketoconazole, an inhibitor, and whatever
happens with that result, you can translate to the
others.
When a study was conducted such as a
cyclosporin study, and with rosovostatin, when we
couldn't translate that in the labeling, we only
said when cyclosporin increased rosovostatin by
sevenfold, and therefore, the initial dose should
be this, and we do not translate that to others.
So until we know more, then, I think we
will be able to put in the table and put in the
guidance you're suggesting.
DR. DERENDORF: I'm very happy to see that
induction is addressed, and that was overdue in
both in vitro and in vivo. Now, in the in vitro
part, I have a question: it says if 40 percent of
positive controls suggest possible induction
potential, does that mean, first of all, 40 percent
of what? What will be the measure? And the
positive control will be defined, because
otherwise, you can change, you know, the percentage
246
based on your control.
DR. HUANG: Yes, you will hear more from
the subsequent speakers, but I can say in our
guidance, we--sorry, concept paper, we did
recommend that, for example, with CYP3A, you look
at revamping induction, and we use the enzyme
activity, the fold increase in enzyme activity. So
if it's increased tenfold, then, 40 percent would
be fourfold.
DR. DERENDORF: With respect to the in
vivo, you have the classification of strong and
moderate with two and fivefold increases in
exposure. If we apply that to induction, would
that mean that a fivefold decrease in exposure
would also be the border between moderate and
strong?
DR. HUANG: Well, we did propose that at
the April Committee meeting last time, and the
comments from all of you was that we don't have
sufficient data to indicate which one is a strong
inducer, and we just don't have the information.
But I'll be happy to revisit that if the Committee
247
thinks it's proper that we do that.
DR. HALL: Yes, could you comment
on--you've done a really good job of talking about
when to conclude something is an inhibitor, but
when it came to concluding that it was not an
inhibitor, you somewhat skirted around that. And I
think, you know, there are clearly labeling
advantages to being able to conclude it's not. You
mentioned you have no recommendation, but the
former working group did come up with a
recommendation.
And it seems like that would be an
important thing to address.
DR. HUANG: Well, I'd love to hear the
Committee's recommendation. The PhRMA white paper,
as far as inhibition, it says if I over KI ratio is
more than 1, it's likely; if it's between 0.1 and
1, it's probable, and I believe it's--when it's
less than 0.1, it's at least--well, I don't
remember the exact words, but it's not likely. And
we do have, we have cases where the ratio of 0.1,
you still see some interactions.
248
So it is difficult to say--I mean, rare
occasions to say that it directly translates,
especially for 3A, since the inhibition, I mean,
the induction could happen--I'm sorry, fall back;
inhibition could also happen in the GI tract. So
when you use the equation, you might be able to
come up, to derive an equation to say, well, 0.1,
it's going to result in very small extent of
interaction.
But if you consider the other components
in the GI and also the uncertainty of the
concentration in the hepatocyte as compared to what
we are using right now, plasma concentration, and
that's why we are using a more conservative
approach. We did not use exactly 0.1, although we
did mention when you have a large gap between I and
KI, and we put in the numbers and say if it's
fiftyfold, then, it's not likely there's
interaction. I know it's a very conservative
number.
And that's why we're proposing perhaps we
could use a rank order evaluation. Any time in
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doubt, you probably want to study with the one with
the strongest inhibition, that is, the smallest KI.
And if the in vitro data, in vivo also show no
interaction, then, you do not have to do the other
studies. If there are other alternative
approaches, the working group will be very willing
to listen to the suggestion.
DR. SADEE: Shiew-Mei, I have a comment
and maybe a question about HIV therapy, which takes
advantage of many of the agents that you have shown
to be interacting, so we expect a lot of
interactions. Now, in that case, physicians use
retonavir to, in fact, as a dosage sparing agent;
in other words, you block probably PGP; you block
3A4 and a number of other cytochromes by adding
retonavir; then, you systematically adduce the
other agents because of that knowledge.
Unfortunately, these patients are also
given statins. They're given antineoplastic
agents, antidepressants, you name it. So this is
the inverse usage of the information of inhibitors,
and it appears to me that it has tremendous effect
250
on the adverse effects that are pretty prevalent in
HIV patients. So is this something you also want
to look at, or I was personally very surprised to
hear these relatively nonchalant views of the
inhibitors to spare other agents, whereas, to me,
it would induce a lot more problems.
DR. HUANG: Yes, you mentioned kalitra,
which is a combination of retonavir and lopinavir,
and a low dose of retonavir was used to increase
the exposure of lopinavir to its HIV therapeutic
effect. In that case, there's no difference in how
we treat the evaluation of kalitra as an inhibitor
or inducer if it's submitted today. So we have the
package included many interaction studies based on
that we already know retonavir is a CYP3A
inhibition, and there are many studies that were
conducted because of the nature of the HIV therapy,
and many of these studies, the results were
summarized in a table format, and there's also
certain for kalitra, I think most of the study
results were summarized in tables. I don't think
there's extrapolation of the conducted study.
251
And this is true for most of the HIV
therapy. When you submit a new molecular entity,
this drug's effect on others will be evaluated as a
standard procedure almost the same as what we have
described in the concept paper. If you're going to
evaluate multiple inhibitors, how that would
effect, and I think there's some ongoing research
project that we hope to conduct using modeling and
simulation and just see how different the various
inhibitors or various pathways will result in an
extent of drug interaction.
And the study that we're conducting with
Indiana, and it's only a very first step to looking
at multiple inhibitors of one substrate, how would
that conduct? How would that compare to a
simulation outcome? And what you envision is much
more complex.
DR. WATKINS: You know, that was a great
presentation, and I think it's a great idea to try
to merge the two old documents and come up with new
guidelines, but I suspect to industry, it's not
going to be reassuring that the reason to do this
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is that we can now Web link the different
substrates that could change week to week is sort
of the implication.
But I think the document then needs to
stress the fact that unfortunately, this is still a
work in progress. We really haven't refined the
probes, for instance, for PGP and the issues Cathy
was bringing up of separating out transport from
metabolism and the interactions of transport and
metabolism. And the last thing you would want is
with the publication of this guidance for upper
management in a major pharmaceutical company to
feel that this had been solved and that the
scientists could be put onto other projects,
because there's so much work left to do in the
area.
DR. HUANG: Right, we--the idea of the Web
link tables is, I think, because the last guidance
was published in 1999, and this is not likely to be
finalized until 2005. So it's a six-year gap. And
with the Web link, I think we can do maybe more
frequent than every six years.
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DR. REYNOLDS: I just wanted to address
the ritonavir issue. When a company is evaluating
an HIV droug, and ritonavir will be part of the
regimen, we really consider the drug plus ritonavir
the drug. So if the drug will be given alone, or
if it will be given with ritonavir, we expect them
to look at it both ways, and we consider the
interactions very seriously.
DR. SADEE: On that also, interactions
with statins, for instance, which are very often
given or metabolized and transported by very
similar gene products.
DR. REYNOLDS: Right, so we would expect
to understand the interaction of the protease
inhibitor plus ritonavir on the statin.
DR. BLASCHKE: I think coming back to
Wolfgang's point, as you're saying, I think,
virtually all patients who are getting a protease
inhibitor for HIV are also getting ritonavir, and
what I think it speaks to is probably the
importance--and they're also getting these multiple
other drugs, whether they're statins or CNS active
254
drugs and so forth, and it probably really speaks
to the importance of most drugs in which we think
there's any possibility of using that in
HIV-positive patients, that the ritonavir should be
one of the drugs that is studied rather than some
alternative.
DR. VENITZ: One comment: as you know,
I'm very much in favor of using this approach to
minimize the amount of studies that need to be
done. One concern that I have, and I mentioned
that before, is whenever you talk about dose
adjusting based on either inhibition or induction
data, you're basically trying to match areas under
the curve or something like that for the parent
drug.
What you don't necessarily consider, and I
suggest you incorporate that in your paper, in your
guidance, the change in the metabolite profile.
You're reducing the dose. It's not the same as
inhibiting a particular pathway. You all of a
sudden have a metabolite in higher concentrations
than it would be, okay? So I'm not sure whether
255
that's relevant for specific drugs, but it may well
be, depending on whether the metabolite contributes
to activity, meaning safety or efficacy.
But it's something that I haven't seen in
any of the documents that you've provided us.
DR. REYNOLDS: Correct, yes.
DR. VENITZ: Okay; any other comments or
questions?
[No response.]
DR. VENITZ: Then, thank you, Shiew-Mei,
and our next speaker is Dr. Keith Gottesdiener from
Merck, who's going to give us the scientific
perspective.
DR. GOTTESDIENER: Thanks very much for
inviting me here today. Before I start, I'd just
like to also let you know that many Merck
colleagues helped me to put this talk together, and
I just wanted to acknowledge some of the people who
had actually worked on this talk as well.
It's a real pleasure to be here today.
I'm in charge of early development and clinical
pharmacology at Merck, and to a great extent, what
256
I do or a major part of what I do every day, every
month, every year is really looking at this
question from inside the industry as opposed as to
from outside. Of course, the FDA is very
interested that the packages we put together and we
submit for registration of a drug be complete.
In a sense, I get to do that sometimes
months and years ahead of the FDA, and it's really
my job to really make sure that package is robust
and to try to put it together. And so, in a sense,
I think that both myself and the people in the
industry who do these kinds of things have a very
unique perspective. We get to see a lot of
compounds that never really make it past this
evaluation stage as well as those that actually go
forward to filing, and I hope I'll share some of my
thoughts with you today.
I can assure you that senior management
does not think that this problem is solved yet
today, and I'll point out some of the issues. I
wasn't able to really participate in the last
meeting where you talked about induction, but some
257
of the questions that came up to Shiew-Mei are
exactly very similar to the kinds of questions that
I would pose as well: how difficult it is
sometimes to do this in a real life situation.
So what I'm going to do is talk just a
minute about the approach to assessing drug
interactions. I'll talk about the many areas of
agreement with the concept paper that exist, which
I really have to applaud. It's a real step
forward. I'll mention a couple of areas where I
think there's really some further discussion, and I
just pick three today: induction, transporters,
and this issue of multiple inhibitors, multiple
impaired.
I'm not going to cover specific comments
on the concept paper. I do have many. I've shared
some of them with Shiew-Mei as well. The study
designs, the tables, et cetera; when that comes out
as a draft guidance, I'm sure I'll have plenty of
opportunity to comment, and nor was I going to
spend much time talking about specific comments on
the questions to the Committee.
258
What I wanted to do was focus on the
approach to some of these issues. When I think
about approaching, assessing drug interactions, I'm
really probably saying this slide or two, I'm
probably talking to the wrong audience. I often
have to explain to people what the approach is.
But clearly, the issue is how should we adjust the
dose of a substrate drug in the presence of an
interacting drug? And which DDIs and which drug
interactions to study, how to answer that question?
And clearly, we're moving from the past,
when this choice was largely empirical by the
likelihood of coadministration, clinical
consequences of the interaction towards a
science-driven approach, particularly where
feasible. You know, we're using preclinical in
vitro studies to determine in vivo studies, in vivo
studies using probe substrates and really robust
study designs. But clearly, I think there's ideas
where the science is evolving and the necessary
tools and the probes are still lacking.
We also think it's important, again, like
259
the FDA, that there be prespecified criteria to
compare the PK or PD measures to the drug in the
presence and the absence of the interacting drug,
and clearly, this is based on the safety and the
efficacy profile of the substrate drug, the
therapeutic index, the clinical context of the use
of the drug, which I think actually is quite
important and very hard to capture in the guidance
and the concentration and response data for the
substrate, which is obviously something this
Committee is very interested in, and so are we.
One thing, though, I do want to emphasize
is often, this is not clearly positive or negative.
It's very difficult if something is or is not an
inhibitor; it does or does not have a clinically
relevant effect on one drug or another, and
actually, probably, the one comment I'd make about
the questions today, it will probably be the only
one, is the questions are really framed as
either-or. If it is an inhibitor, this is what you
should do.
And in many cases, I think the guidance
260
the Committee is going to give, and it's going to
be quite interesting; my problem is trying to
decide is it an inhibitor or not in many ways, and
I know that the FDA struggles with that very
question. For the NCE or the NME, the data is
often quite limited; concentration response info is
always better for efficacy than it is for safety,
and I still think there's many areas for probe
substrates, where there really isn't much
consensus, even though I think we've come quite
far. And as I'll point out today, induction in
particular is problematic.
But let me talk first about all the good
points. I think that the integrated and scientific
approach is clearly the right step forward. I
think we've made a lot of progress and clarity on
CYP interactions, especially the in vitro-in vivo
correlations and the clarity on the substrates,
inhibitors or inducers, though I do have to
comment: somehow, simvostatin is on the list of
sensitive inhibitors twice, and I didn't know if
that was a hint from the agency to Merck or not or
261
whether it was just a typo.
I'd certainly agree with the use of PK in
poor metabolizers where appropriate. I think the
robust study designs is really important, and in
many ways, I applaud the efforts and the question,
the slides that Shiew-Mei showed, for example, on
doing a ketoconazole interaction study. Having
read that literature for many, many years and
struggling with that issue day by day, the issue of
whether you're going to do 200 and 400, whether
you're going to dose one day, three days, five days
or a week, those are real issues that have real
impact on how the results come, and it's all too
easy to pick a study design that really will, in a
sense, manipulate the result so that it comes out
the way you'd like it to rather than the way it's
most scientifically correct.
So I think really, we're going to be in
much better shape as we start to look at robust
designs and receive, you know, gain a little bit of
clarity on which ones really give us the best
information.
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I also applaud useful and consistent
labeling language. Part of my job is to read to
every new label that comes out and see what the FDA
says about every new drug, and I understand the
desire to be consistent, really quite hard in the
field of drug interactions, and I'm always so
struck about how difficult that is. And of course,
then, I also get to compare it to what happens in
the EU and the rest of the world, where a whole new
variety of approaches come forward as well.
So I think that this is a real step
forward, but I do think there still needs some
discussion on how to label moderate inhibitors, how
to define sensitive CYP substrates, and I must
admit: all the devil is in the details. So while
I agree with the principles the FDA has said, it's
really going to be what's in the tables and how
it's translated into labeling language, I think,
that I'm going to be very curious to see.
So let me talk now about some of the
issues that I think are worth discussing, where I'm
not sure I fully agree with the concept paper or
263
some of the issues that you may grapple with today.
And I think about things very, very practically.
You know, where are we today with in vitro
predictions of in vivo drug-drug interactions? And
I think ready for prime time. You know, we really
understand where we are; things related to CYP
inhibition, particularly for the five major CYPs.
I think almost ready for prime time are
some of the PGP interactions, UGT and some of the
other CYPs, I won't talk about them today, and CYP
induction. And there, actually, I think there are
some issues with the tools we can use in vitro, but
I also think there's many more issues actually in
the in vivo studies that follow, because in the
end, as I look at this, it isn't only an interest;
it isn't only of interest to me to try to predict
from in vitro what is going to happen in vivo, but
there's also the issue of how do I interpret what
happened in vivo, obviously, into something that's
useful, so that we can actually use the drug
properly?
And then, I really think that many things
264
are not ready for prime time, though I applaud the
science moving forward. Most transporters, to me,
still are in this gray, murky area where I have a
very difficult time understanding how to use them.
And I'll also point out some of my difficulties
with multiple paths of inhibition as well.
So induction, I don't have to talk to you
about. There's a lot of concerns for induction.
Mostly, it's related to the reduction in
therapeutic efficacy. Auto-induction is also a big
concern; rarely the imbalance between toxification
and detoxification. It's dose and time dependent.
The study designs become really quite important
here. It's dependent on clearance and route of
administration. Again, a study design issue, and I
should also point out it's a concern with both
initiation and discontinuation of an interacting
drug.
We have many models or many tools now to
talk about CYP induction, and animal models were
previously used. You know, it wasn't that long ago
that that happened. When I arrived at Merck nine
265
years ago, the only way we really assessed
induction was by doing high dose, short-term
studies in rodents instead of looking at liver
weights and science of induction.
You know, nine years is a very short time.
And today, we're talking about, really, a whole new
category of tools. Dr. LeCluyse is going to talk
about that. But clearly, those were poor
predicters. We looked at those, and we shrugged,
and we went ahead into the clinic, and we had no
idea what to do with the information.
Nowadays, the in vitro models are much
better: the assays, the primary culture of human
hepatocytes, and they're very, very--clearly, very,
very helpful in the selection of drug candidates.
And in fact, in many ways, that's where their most
helpful nature is. We rule out enormous numbers of
candidates, because they're really positive in
these assays overall.
But I will also tell you it isn't always
that easy. It sounds like it's great: you set a
criteria; you cross off a drug candidate, and you
266
move on. As targets become more complex, the
chemistry becomes more complex; the size of
molecules increases, more and more whole areas of
structures actually carry some risk of induction.
So in many cases, we're not able to cross off those
candidates, and we have to bring them forward into
the clinic.
But the problem I have is still is it
quantitative in vitro-in vivo prediction possible
for induction? And I think there's many factors
that complicate that in vitro-in vivo
extrapolation, particularly inter-individual
variability; plasma protein binding; multiple
mechanisms as well.
Now, I wanted to share with the Committee
some idea of what I actually see as a
vice-president of clinical, you know, pharmacology,
drug development. This is the kid of data I see.
These are hypothetical drugs. None of them is
real. But they're all based on drugs that actually
have made it into the clinic. And as you start to
look at this, you can see some of the things that
267
come forward and some of the complexities.
I picked five drugs where the mouse
five-day study was actually negative, okay, just to
sort of get that off the table. You can see the
human PXR data, the mRNA data. Those are percent
activity of a rifampin control at 10 micromolar;
the enzyme activity in human hepatocytes, and I put
over on the side something that I also think is
important is really what the CMAX concentration was
in the clinic. Sometimes, that's a predicted
value; sometimes, it's an actual value when we get
into the clinic, and we understand efficacy.
And you can see, if you looked at any one
of these drugs here, the question about should we
or shouldn't we do an in vivo induction study is
really quite difficult. Now, I wish I could tell
you what these five drugs were. More importantly,
I wish I could tell you what the results of, for
example, Midazolam studies were for those five
drugs. Many of them have not progressed far enough
in the clinic to have that evaluation, but this is
the kind of data we grapple with every single day.
268
And the question I ask myself is which
ones really need an in vivo study? And I don't
really know. So at present, I could probably only
say that we can predict a likelihood of CYP
induction; highly possible on one hand; less likely
on others. And I kind of gave some examples of
things where at least they fell into the possible
range going forward, and most likely, we would have
done an in vivo study to follow up what's going on.
I should also point that clinical data
does sometimes help. For example, we see--often,
we see evidence of autoinduction, which helps to
clarify the issue in a particular clinical dose.
But I think once again, it really depends to some
degree on what kind of exposures one has in the
clinic, and that helps in some ways to really
interpret the data.
Now, of course, I think that's the easy
part. I think the hard part is actually
interpreting an in vivo study. I think there's
less consensus on probe substrates, their clinical
interpretation. I wasn't here for the Committee
269
deliberations last time about the issue of
induction, but I find these questions quite
difficult.
And this is just a slide showing the
percent of baseline exposure for a variety of known
inducers. I don't think you have to pay attention
to the specific data. Many of these were studied
on numerous occasions. But this is the effect on
oral Midazolam. And I look at this data, and I'm
asking myself really, is this where we think the
bar should be? This is just about a fivefold
decrease, or should the bar be here? We know the
glucocorticoids and St. John's worts do have
clinical effects on certain drugs, or where should
it be?
And in the end, I still struggle with
really the interpretation of induction, whether
it's the in vitro or in vivo going forward. Now,
more recently, the role of transporters has been
recognized, and I think there's clear examples of
transporter-mediated drug interactions. A couple
of years ago, I don't think I would have actually
270
said that there were clear examples. I would have
said hypothetical or potential examples.
And I certainly think the understanding of
peak lack of protein is advanced greatly. But the
in vitro methods are not really standardized, and
they're not really quite as available as we'd like.
And I think a quantitative in vitro prediction of
in vivo relevance is still quite difficult. And of
course, it's complicated by the fact that the
transporters really are just not an issue of
metabolism but also absorption, tissue
distribution, excretion; as someone said earlier,
the whole pathways can be involved as one is
looking at this influx, eflux, et cetera.
Now, probably peak lack of protein is the
best study, and I don't have to say much to this
particular Committee about that. But even there,
the in vitro methodologies are not quite what I
would like. The transgenic MDR naga mice are a
very powerful tool, but we have numerous examples
where the human and rodent differences occur.
The in vitro tools are clearly becoming
271
more sophisticated, but some of the PGP substrates
don't follow simple kinetics. There's a lot of
overlapping substrates between PGP and CYP3A4, many
inhibitors affect both, and of course, there's the
issue of other transporters as well. The tools are
most useful to identify PGP substrates. We can
certainly identify PGP inhibitors, but it's still
comparatively laborious and time consuming to do
so.
And what might I, as a clinical
pharmacologist, actually get as an evaluation of a
PGP substrate? This is a paragraph, actually, from
a real drug. I changed the numbers once again to
make it a little hypothetical, but you can read
this. What we see is what happens in the MDR mice.
We can look at transport ratios going back and
forth. I have a B to A ratio from the two sides of
1.7. I'm not really sure if that's a substrate or
not; what should I do with that particular data?
Now, if an in vivo study is indicated, and
I've told you I struggle with what that actually,
you know, how do I actually decide that, I think
272
for assessing a potential PGP inhibitor, digoxin
clearly is a suitable probe. I do think that most
other probe PGP substrates are less than ideal.
But I've borrowed a slide from Shiew-Mei
just to talk about some of the difficulties I have
about thinking about assessing PGP substrates.
This is the same slide that Shiew-Mei showed
before. These are all PGP inhibitors, and you can
see in vardenafil what the tremendous difference
there might be between all those, and of course,
part of the difference is that ritonavir, as we
pointed out, oops, doesn't work, ritonavir, as we
pointed out, clearly is an inhibitor not only of
PGP but of CYP3A4, but in this particular case,
it's also an inhibitor of 2C9, which is probably
the other pathway by which vardenafil is actually
metabolized.
And you can see there's a widely divergent
variation in terms of the results one would see.
I'm not sure here that I think that that's really
the kind of data I'd like to be generating to help
understand how to extrapolate datas to new
273
situations.
I think the situation in terms of
inhibitors and doing a study on a substrate with an
inhibitor is even worse. If you look at the
compounds that we have that are inhibitors, there's
quinidine, ritonavir, verapamil, cyclosporin, okay?
These are all very difficult compounds to work
with. We don't use quinidine in volunteers. We
really think it carries too much risk. Ritonavir,
as I've already mentioned, is a 3A4 PGP substrate,
inhibits 2C9.
We've had studies where we've seen
tremendous induction of UGTs, a whole variety.
Some have gone up, some have gone down. In the
end, when we do studies with ritonavir, what we do
is we conclude this is what ritonavir does and
nothing else, because we really just don't know how
to interpret the individual data.
Verapamil, also very complicated; similar
on PGP and CYP3A4, but we stopped using it in our
clinical trials. When we gave it to volunteers,
Dr. Vago in the back there who used to be at Merck
274
did studies for us where we showed that we clearly
saw, you know, PR lengthening in all of our healthy
volunteers, and we just really thought that the
risk-benefit really wouldn't allow us to do that.
And of course, cyclosporin has myriad
effects. The interpretation is difficult, but it
carries a significant risk to volunteers, and we've
been unwilling to do more than single dose studies
in volunteers because of the effects it has on the
kidney and on immunosuppression. As a matter of
fact, this is very real to me. Last Friday, Merck
spent a couple of hours, a whole crowd trying to
design a study requested by the agency to really
try to understand the effect of a model PGP
inhibitor, cyclosporin, on one of our drugs, and we
just found it almost impossible to design a study
that we thought would really be able to answer the
question without significant patient risk.
Other transporters are far less
standardized and available. Many cell-based
systems contain multiple transporters, making it
hard to interpret in vitro. There's few
275
well-defined substrates and inhibitors. The
correlations are difficult. Many of the
interactions can't even be linked to a single
transporter system. And we just don't know how to
generalize these.
So I think that in general, my feeling
about other transporters are that the science
doesn't support an in vitro-in vivo correlation.
Clearly, we're moving that way. I have high hopes
that five years from now, if I stood in front of
the Committee, I'd have a different answer, but
this is what I think today.
Now, I wanted to just close and talk a
little bit about the multiple inhibitors, multiple
impaired. Just like with induction, Dr. LeCluyse
is going to be talking about that; someone is going
to be giving a presentation about this as well, and
I think there's some really elegant work there.
But I have to admit, I'm not a big fan of this
particular approach. I understand the agency's
desire for higher exposures when evaluating QTC
issues, which I think is probably the primary
276
driver for many of these studies.
But the new hurdle for QTC is very, very
stringent. And we certainly agree, I certainly
agree that the margins are critical. But the real
question I ask myself is for how many of the drugs
that are coming forward are extraordinary efforts
justified? And of course, not everybody would
agree with me that some of the things that we're
doing with multiple inhibitors are truly
extraordinary efforts.
But I want to just lead you through a
little bit about how this actually works in
practice you can understand why I take that
approach. First of all, the QTC effects of many
inhibitors are not well-characterized. That's a
solvable problem. And again, I hope that in a
couple of years, we'll know that ketoconazole and
itriconazole and, you know cyclosporin or whatever
we're going to use in these studies, ritonavir
really has no effect on QTC that could mess up
these definition QTC studies.
But the important thing to realize is
277
while the industry agrees with all the agencies
around the world that these studies are important,
these studies are extremely costly and difficult to
do, and the carrot to the industry, okay, is the
fact that if we do these right, and we get an
answer that really satisfies the agency that this
drug does not have a QTC effect, we really need
that information to prevent us from doing
extraordinary efforts in terms of monitoring in
phase three. So it kind of puts a limit on when we
need to really have this data to be most useful in
terms of designing a QTC study.
If it isn't available for us at the end of
a phase 2B study, honestly, it's much less valuable
to us overall. And so, we have to work hard to get
that in. Now, what do we have to do to do a
multiple pathway study? In most cases, we have to
do a clinical study first to really define the in
vivo metabolic pathways. It takes nine months to
set up, six months to analyze. We need clinical
data on each inhibitor separately, really, to
understand the usefulness to increase PK exposures.
278
We have to get that data, we have to model it to
make a prediction what is going to happen when we
look at multiple pathways.
And in most cases, I would argue, you
actually need to test the concomitant
administration of the inhibitors before the QTC
study because of the issue of safety and
tolerability. These studies are not really done at
sites that are really set up to carefully evaluate
sort of phase one type issues, and in many cases,
you'll be giving a new exposure to drug that no one
has ever seen before.
And of course, these QTC studies get quite
complex if people feel dizzy or nauseous or vomit,
have diarrhea, okay? I have to tell you: I am
senior management, but if I went back and said we
couldn't complete our QTC study and that a million
or two dollars are really down the drain because
people were unable to tolerate the drug, I would
not be well received. And so, we have to do that
stuff as well.
Special populations also are needed in
279
some cases, and I think there are some elegant
studies, like the telithromycin study, because
recruiting those particular people is really quite
difficult and time consuming as well.
Now, to make it even worse, those are
logistics issues. This is what I might see,
actually, from a particular drug where we're
considering a multiple pathway. And this is,
again, patterned after a real drug. In vitro data
incident that 3A4 plays the major role, but there's
10 percent from four other CYPs. What inhibitors
should we use? How should we actually design such
a study?
And lastly, I also question are we really
as smart as we think? Despite all our knowledge,
can we really predict the effects of inhibition of
multiple pathways? And I just wanted to give one
example of some data that will be presented at
ASCPT the next year about a study we were asked to
do, which I think was actually a very good study to
request, so I certainly support it, but one where
it showed me that I was a lot less smart than I
280
thought I might have been.
Aprepitant is a moderate CYP inhibitor.
It's used in combination with 5HT3 antagonists, and
dolasetron is a 5HT3 antagonist we had not studied
in our clinical program. It's metabolized by 2D6,
with 3A4 being an important pathway. And because
of the concern of QTC prolongation with the
dolasetron, we did a study at the agency's request
to conduct an aprepitant interaction study in 2D6
extensive in poor metabolizers.
All of the data that we had would have
suggested we should have had a remarkable effect.
And in that study, as you can see from that data,
if you take a look at what happens with dolasetron,
with aprepitant, APR, and dolasetron together, we
were able to show, in fact, yes, poor metabolizers
do have higher levels. But closing off the CYP3A4
route with a moderate inhibitor really had no
important effect at all on the levels. Very
reassuring in this particular case, but clearly not
what we would have predicted overall.
So overall, I think that we really are
281
making a lot of progress. I very much applaud the
efforts of this Committee and the FDA, and I think,
though, that we're really not there yet in all of
the things going forward, and this is sort of my
summary of what's ready today and what I hope will
be ready in the future.
Thank you very much for your patience.
DR. VENITZ: Thank you.
Any comments or questions?
[No response.]
DR. VENITZ: Thank you again.
Our next speaker is Dr. LeCluyse. He is
the chief scientific officer of CellzDirect, Inc.,
and he's going to talk about induction.
DR. LECLUYSE: Excuse me while we do a
technology switch here.
[Pause.]
DR. LECLUYSE: It worked.
Okay; I also would like to thank the
Committee for this opportunity to speak to you.
The way I interpret my role in all of this is that
I think I'm supposed to condense this labyrinth of
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information that's out there on nuclear receptor
biology and what it all means in terms of human
gene regulation, P450 induction and how to do in
vitro screening for that.
So with that task in mind, let me start
out by just first putting up the questions that
it's my understanding that we are asked to address,
and this is very limited as compared to a number of
issues that Keith brought up and addressed in terms
of the in vitro-in vivo correlations, et cetera,
and some of the complications associated with that.
So I am specifically going to focus on
these questions that were placed in the paper or at
least suggested in the papers, questions that need
to be addressed, such as if a drug's induction
effect on 3A4 in vitro is negative, then, it is
acceptable to not recommend any in vivo studies
with substrates of 3A, 2C9, 2B6 and 2C19, yes or
no?
Also, the other question that was meant to
be addressed today is if the in vitro induction or
increase in enzyme activity is more than 40 percent
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of the positive control, then, there is a need to
recommend an in vivo induction study, yes or no?
I'm going to focus predominantly on this first
question, because I think that's the one that's
most complicated and involves a little bit more of
a mechanistic understanding of what our current
understanding of regulatory of the human liver
genes, and this, you could argue, is as much of a
philosophical one.
So before we can address that specific
question, especially the first one, let's start off
by first reviewing the enzyme induction in humans
as we currently understand it or as observed in the
clinic.
So, for example, if you take compounds,
and certainly, this is not a complete or
comprehensive list, but it serves to represent the
point that for most drugs that are known to cause
clinically significant drug interactions, and
that's the point, our current understanding of
which CYPs are involved in their interaction is
pretty evident these days, especially by the number
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of drugs that we use as probes as well as the in
vitro data to support that.
We also know the relevant plasma
concentrations at which we see a clinically
significant interaction event. And then, also,
now, we're very much aware of the particular
pathways that mediate these events. And notice
that for the most part, these center around three
receptors, namely, CAR, PXR and the AHR. And I'll
go into much greater detail on those in a second.
Another way to look at this is if you
actually look at the inducible P450 enzymes in
human liver, with the exception of CYP1A, which is
predominantly induced by aromatic hydrocarbons,
some dietary components and cigarette smoking and
with the exception of 2E1, which is basically
induced by solvents and drugs like isoniazid but
mostly involves a mechanism of stabilizing protein
and RNA, for the most part, the rest of these often
are induced by compounds represented by the
anticonvulsants, antibiotic rifampin, et cetera,
suggesting that there is some overlap or
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commonality in their mechanism of regulation.
It's now fairly apparent that especially
for the regulation of the human hepatic enzymes,
that there's three major receptors that are
involved: predominantly the aral hydrocarbon
receptor, the AH receptor; constitutive androstane
receptor or CAR; and the pregnane X receptor, PXR.
And there's three main points that I want
to basically draw from this particular slide:
number one, each of these receptors contains a
ligand or drug binding domain which determines,
basically, which drugs are going to activate it,
and also, they contain a DNA-binding domain, which
determines which DNA sequences or response elements
that they're going to bind to upon activation by
drugs.
Now, the other point I want to bring out
is that these all form heterodymers with other
proteins, and for the most part, the AH receptor is
distinct, in the sense that it partners with a
protein called the aral hydrocarbon receptor
nuclear translocase protein. I didn't name it. It
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was given that name a long time ago. The acronym
AHRNTP is given to that.
On the other hand, CAR and PXR both
heterodimarize with another receptor called RXR,
but basically, it's gratuitous in its function
here. It's predominantly driven by--it's the
partner CAR and PXR. Now, the other point I want
to make is that upon activation, each of these
nuclear receptors induces a number of genes, not
just a single subfamily or, you know, a limited
class of genes, but, for example, upon activation
of PXR, you're upregulating a number of phase one
enzymes; also, transporters as well as phase two
enzymes as well as others, including the
carboxylesterases, by the way.
So bear in mind that also, CAR and PXR
share a number of these target genes in common.
So, for example, 2B is upregulated by both CAR and
PXR; 3A4 and the 2Cs, beginning to suggest that
there are some common regulatory mechanisms of
these genes by these nuclear receptors. And we
actually understand now enough about the particular
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promoter region sequences and the response elements
that are in the promoters of these genes to explain
mechanistically now that they can be and ought to
be coregulated by activators of these receptors.
So our first evidence for coregulation
that we observed in my lab, and we've been looking
at this for over a decade, I would hate to admit
now; basically, our first evidence was a study that
we set out to do to explore the effect of 14
different compounds that were known to induce 3A4
to various extents, either in vivo or in vitro, and
our intention was to relate that to their PXR
activation profiles.
Now, interestingly, when we extended those
studies to include 2B6 activity, we basically found
something very interesting, which is summarized in
these tables over here. So if you basically look
at the most potent or the strongest inducers of 3A,
you'll notice that clotrimazole, rifampin and
ritonavir are also very potent inducers of 2B6 in
this particular case.
Notice also in the 2B6 column that there
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is a couple of others, including phenotone and
phenobarbital that are strong 2B6 inducers, but
they're either moderate or weak inducers of 3A;
however, upon more extensive evaluation, even these
compounds are known to induce 3A, here again
showing some common regulatory mechanisms.
Now, if we extend these studies to include
CYP2C9, we also find very similar profiles; for
example, potent inducers of 3A and 2B6 also induce
2C9. Now, this is represented nicely in this
particular slide, where we looked at the
coregulation of CYP2C9 and 3A4 by avasomid, which
we discovered to be a very potent PXR activator.
It's also been shown to interact clinically with
warfarin and midazolam and digoxin.
You can see here in two separate donors,
if you look at 2C9 versus 3A4 in hepatocytes from
one particular donor how the response concentration
curves basically are almost superimposeable. Also,
in a second donor, the same situation, suggesting
here common regulatory mechanisms via PXR in this
particular case.
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Now, if we extend these studies to include
additional inducers of 2B6 and 3A, but then, look
at the induction now of multiple 2Cs, including
2C8, 2C9 as well as 2C19, in this particular case,
we're looking at RNA, not activity, but it still
exhibits the point that I want to make that
basically, all these compounds that are inducers of
2B6 and 3A via activation of CAR and PXR also
upregulate the three 2C enzymes.
The other point I want to make is that the
most efficacious inducers are actually
transactivators of these 2C9 genes have a tendency
to be rifampin and/or phenobarbital in all three
cases.
And finally, the other point that I want
to make, because it's going to play a role in terms
of why we're proposing looking at a limited number
of endpoints is if you actually look at the
induction of 2C9, it's basically between two and
threefold, with even the most potent inducers,
positive controls, if you will, suggesting that
it's actually not a very sensitive target gene if
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you're trying to actually elucidate the induction
potential of a particular drug, and since we've now
discovered that there's a lot more coregulation
between these genes, we propose a more
mechanism-driven type screening strategy than what
has typically been proposed in the past.
So in essence, what this boils down to is
we think we're at a point now where we understand
the regulatory mechanisms of the relevant human
P450 genes to where we can now do a more
mechanism-driven screening strategy with a goal to
screen efficacious activators of these particular
dominant nuclear receptors and these clinically
relevant induction events where we propose
screening protocol using a sensitive endpoint for
each nuclear receptor being the goal with the
premise that potent activators of each of these
individual nuclear receptors will induce a number
of target genes but differentially.
So for example, potent PXR activators will
induce 3A, 2B, the 2Cs, even some of the phase 2
enzymes like 1A1, UGT1A1, transporters like MDR1,
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but 3A4 is the most sensitive. Likewise, potent
CAR activators will induce a number of these same
genes that overlap with PXR, but 2B6 is the most
sensitive. And then, finally, potent AH receptor
agonists will induce 1A2, phase two enzymes such as
UGT1A1, GSTs. But 1A2 is the most sensitive in
terms of screening for that.
So, finally, an example protocol that we
would advocate, and we currently use, is to treat
human hepatocytes. That's a given with our
protocol. Treat with a new drug at three to four
relevant concentrations, especially where
clinically relevant concentrations are known; treat
for one to three days; include positive controls,
which is very important in terms of making
appropriate comparisons, so, for example, the most
robust 1A, 2B and 3A inducers ought to be used for
positive controls, in our opinion, where some sort
of maximum is obtained that's possible with the
particular preparations of cells.
Now, one has the ability to measure RNA,
certainly, protein as well as enzyme activity. We
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would advocate that the enzyme activity is probably
the best representation of the induction response.
Protein content is semiquantitative at best, and
the relationship between RNA content and enzyme
activity is still yet to be completely
characterized, although I think we're nearly there.
And finally, the last point here is that a
major CYP target gene for each nuclear receptor
ought to be the focus of these initial screens; so,
for example, looking at CYP1A2 as an endpoint for
AH receptor agonists, 3A4 for PXR, and possibly 2B6
for CAR, although all 2B6 inducers and CAR
activators that we've come across thusfar also turn
out to be inducers of 3A4.
So finally, one other point that I want to
make in terms of looking beyond enzyme activities,
in this particular case, where we're looking at a
mechanism-based inhibitor such as ritonavir, if you
limit yourself to looking at enzyme activities,
which is the case in this particular study, where
we evaluated seven different inducers of 3A, you
can see that if you only evaluate things on the
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enzyme activity, which is normalized enzyme
activity to the negative control, here, you can see
that ritonavir actually knocked out the activity
significantly in these microsomal assays that we
did. And as we all know, ritonavir is one of the
most potent mechanism-based inhibitors that we've
come across.
However, if you actually were to look at
its effects at the ability to upregulate 3A4 gene
expression at the RNA level, you'd find that
ritonavir is every bit as efficacious as positive
control rifampin at that level, suggesting that
it's actually a very potent PXR activator and
inducer.
So finally, some of the other important
factors to consider in terms of study design: the
interdonor differences in the control and basal
activity between preparations of hepatocytes can
often be a caveat. We suggest that that's why it's
important to compare it to a positive control
rather than fold over a negative control. We also
believe that it's possible that depending on how
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high the basal activity is, it may exclude some
preparations of hepatocytes from maybe being
appropriate for induction studies.
Also, the relevant concentration range of
your drug is important, focused on plasma and
tissue concentrations; appropriate choice and
concentration of a positive control is an important
consideration; certainly, the major species
differences have to be acknowledged in terms of
nuclear receptor activation as well as induction of
specific P450s, so for example, it still surprises
me that some of the studies that I come across
where dexamethasone is still used as a positive
control in human hepatocytes, it's a very potent
inducer, as is PCN in for rodents, but there's
about an order of magnitude difference between
dexamethasone's ability to induce the 3A enzymes in
human hepatocytes compared to, let's say, a
positive control like rifampin.
Also, the expression of the data in the
relevant endpoints is very critical, and that's
been also an issue that's been addressed and
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relating that to a positive control. Exposure time
is important, especially for the particular
subforms that you might be evaluating, shorter for
CYP1A, for example; longer for 3A; and then,
finally, one must bear in mind that solvent effects
on P450 expression and activity are observed.
DMSO, for example, is an activator of PXR itself at
sufficiently high concentrations, and also some of
the alcohols are known to even inhibit some of the
P450s.
And finally, just in summary of the key
points: our mechanistic understanding of enzyme
induction in human liver has increased markedly in
the past decade. Most inducible human P450s, UGTs
and transporters involved in DDIs are regulated by
a few receptors, namely PXR, AH receptor and CAR.
Screening for potential inducers during drug
development, in my opinion, can be achieved using a
single, selective and sensitive target gene for
each of these nuclear receptors through following a
3A4, 1A2 and/or 2B6, and activity data from in
vitro induction studies for a new drug should be
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normalized to a negative control, compared to an
appropriate positive control at appropriate
concentration, considered significant when they are
greater than or equal to 40 percent of the positive
control, and that's actually a question that I'd be
interested to hear others' opinion on that and also
complemented with protein or RNA data if time
dependent inhibition is involved.
So, with that, I'll be happy to answer any
other questions that you may have.
DR. VENITZ: Thank you, Ed.
Any questions for Dr. LeCluyse?
Go ahead.
DR. HALL: Ed, one of the biggest concerns
with hepatocyte work has always been the
preparation, the treatment, the handling, and the
sort of somewhat unique capabilities of one group
versus another group in just the way the
hepatocytes work. Do you believe that is now
sufficiently robust that this can be done
independent of supplier, source of the liver,
they're all going to work?
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And if they are going to work, how many do
you have to use in order to come up with a reliable
answer?
DR. LECLUYSE: Yes, that's an excellent
question, and I think that's been part of the
historical issues with the use of hepatocytes is
depending on whose hands the studies are conducted
in, you can get some variability. And I think that
goes back to how important the study design is and
the appropriate use of the positive controls as
markers or indicators of whether the studies have
been appropriately done, and I think, you know, I
think John is going to maybe discuss that a little
bit more in terms of those criteria, but I think
we're there now to where we can start stipulating
those issues and at least minimize poor results.
And personally, I think you're pretty much
going to have a good indication as to whether your
drug stands a possibility of being an inducer in
three to four preparations of hepatocytes. So I
think if you get--certainly, in this case, where
we're talking about negatives, if you haven't seen
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induction in three preparations of hepatocytes
where you've gotten adequate and sufficient
induction with a positive control, then, I think
you can pretty much rule that out so--
DR. HALL: So to sort of follow up that,
the 40 percent number seems reasonable, but is this
40 percent N statistically significantly different?
I mean, if you had a 0 of 40 and an 80 percent
change, is that okay, or how would you deal with
that issue?
DR. LECLUYSE: Is that between donors--
DR. HALL: Yes.
DR. LECLUYSE: --you're talking about?
Yes, and it is very possible that you may get that
kind of variability, although it may not be that
significant, but, you know, certainly, you may get,
in some donors, and it may be on the border; less
than 40, certainly.
And I think to me, it's more about the
potential. So if you've got one donor where you
exhibit greater than 40 percent induction, then,
that's letting you know that your compound
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certainly exhibits the appropriate properties; that
it's likely or stands a chance of inducing, at
least assuming that your study was designed around
appropriate, you know, in vivo or physiologically
relevant concentrations, it stands a chance of
inducing.
So, you know, I mean, we can go into a
long dissertation about why it may be lower or
higher in certain donors, but certainly, if you see
it in a single donor, then, you know, greater than
40 percent, then, that's telling you what you need
to know, I would argue, so--
DR. SADEE: My question is a little bit
along the same lines. You have a basal activity of
transcription of all of these genes, which is
usually reduced, and those are a whole set of other
transcription factors like the HNF transcription
factor family, and if you have a high expression of
those, your induction will be percentagewise much
lower. So in vitro, you apparently exclude those
where you have high basal activity.
But I wonder whether, in extrapolating,
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then, the data you obtain with hepatocytes in vitro
which have minimal basal activity to the in vivo
situation, that you're not somehow exaggerating the
importance of induction compared to the situation
where you have reasonably high basal activity,
which may be more prevalent in the in vivo
situation, and variability actually comes more from
basal rather than from induced activity in vivo.
DR. LECLUYSE: Yes, I mean, I think
obviously, that's a very good point. In fact, the
one thing I like personally about the use of human
hepatocytes is you do get some feel for what that
range may be in the clinic, because I think they
are representative of true donors. And so, you
know, here, again, to me, it's more about getting
an indication as to whether you should--whether a
compound is going to stand a chance to be an
inducer in an in vivo setting and about whether
you're going to get a negative or not, not about
what do you do when you get to a positive? I mean,
that could be another whole discussion we could
have, which I'm happy to engage in.
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But you know--
DR. SADEE: Do you have any information on
the interaction between, let's say, HNF4-alpha with
a CAR, or are they additive, or do you have any
feeling for this?
DR. LECLUYSE: Yes, they're supportive.
You may be aware of Richard Kim's data as well as
that of others now that suggests that there are a
number of transcription factors as well as
cofactors that are supportive or even necessary for
a normal induction event to occur. And so, it's
almost the equivalent or the way I look at it is
all of these factors are necessary to drive the
car, so in other words, in order for you to get in
your car and drive down the street, you have to
know that your engine is working, the tires are
okay, et cetera, et cetera.
So without any of those things, you may
not get very far, either, but what's driving the
bus, basically, or what's critically driving it is
these nuclear receptors. So something like
HNF4-alpha, as well as other cofactors and
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transcription factors, are necessary for just the
normal events to occur. If anything, that argues
the point of why human hepatocytes are a relevant
model, because they retain their normal profiles of
those factors, cofactors, transcription factors
that I think is actually written in the concept
paper as to why cell lines, for example, might be
inappropriate.
But you're exactly right: I mean, all
those things that just go into factoring maybe some
of the donor differences in how the hepatocytes and
in vitro setting respond, they're also operative in
vivo, so, you know, like I say, to me, what I like
about it is that it's probably more reflective of
what you're likely to run into in vivo.
DR. WATKINS: Ed, as you know, I'm a big
fan of cultured human hepatocytes, but there are
some practical issues as an academician. We find
it very hard to get human livers. And I don't know
if that's been solved by cryopreservation, but
clearly, it's, I think, a limited resource that's
very expensive if you talk about doing all these
303
validations and multiple, you know, with multiple
donors' hepatocytes and doing multiple experiments.
And, of course, there are problems when
you culture human hepatocytes, which is they no
longer have canaliculi, so all the canalicular
transporters presumably just spread out over the
basolateral membrane. So some of the theoretical
advantages of having the relevant cell with the
relevant transporters, I think, is gone, and I
would imagine can be deceptive.
So one of the questions is now that you've
whittled it down to basically two relevant
receptors or maybe three with two endpoints, I
mean, wouldn't the first step be some sort of in
vitro transcription factor activation or transgenic
mouse or something to actually look at the effect
of your compound on the transcription factors
directly rather than marching right into human
hepatocytes?
DR. LECLUYSE: Well, yes, in fact,
exactly. What you've described is exactly
generally what industry is doing is they're
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starting with the least common denominator, which
is the nuclear receptors. And whether their
compounds either bind to or transact or activate
the nuclear receptor, you know, these reporter
assays, as you know, full well, people are using
fairly extensively.
But the relationship between nuclear
receptor activation and a reporter assay and how
that translates to, then, an hepatocyte assay and
then, further yet, in vivo is still, I think, a
long ways from being clear. I actually view them
as nice, complementary tools. I mean, you're going
to get a lot of information from using both to
complement one another, in my opinion.
But back to your point, Paul, about the
availability of resources. You know, that has been
limiting for both industrial scientists as well as
academic to do these kinds of studies, and we're
slowly making headway on that both in terms of more
sensitive assays, where we can do maybe what used
to could only be done in a petri dish, we could now
do in multiwell plates, much more high throughput
305
fashion.
We are, I think, on the cusp of being able
to understand the relationship of the RNA, level,
changes in RNA levels with those of activities, so
that allows you to even make these much more rapid
throughput assays much more amenable to less
material being used and all those things. And
also, you mentioned cryohepatocytes. There are
batches of cryohepatocytes now that are available
to do these studies, so you can basically stock up
on those, if you will, or have better access to
whole donors where they would be available to
multiple investigators or multiple departments
within the same institution or company.
And that's oftentimes what companies have
turned to now is just buying whole lots of
cryopreserved hepatocytes that do plate out and are
inducible and respond well to positive controls to
doing their screening. In our understanding of
what makes a good cryobatch of hepatocytes that
will then attach has advanced significantly, too,
from years ago, so--
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DR. WATKINS: If I could follow up, I
mean, I think the data undoubtedly exists, and you
may have it, but it would be awfully nice to see
stories of drugs that were positive for the in
vitro transcription assays, and you went into
hepatocytes and more negative or vice versa and
then went into man, and it turned out hepatocytes
were the right answer and well worth the resources
and, you know, provided all this additional
information.
I just have not seen that kind of data put
together that would at least from my perspective
justify recommending human hepatocytes as somehow
muscling to the front and an assessment of
potential drug interactions.
DR. LECLUYSE: Let me tell you off the top
of my head the reason for it is remember, these
nuclear receptor assays only evaluate a single
pathway at a time, and we actually do not have a
good assay for human CAR that's similar to the
reporter assays that exist for PXR. And we do, for
a fact, know that there are compounds that
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induce--that are 3A4 in human hepatocytes actually
to the same degree as rifampin that show up as
negative in a PXR assay.
So I think, you know, like I say, the
technology just needs to come along a little bit
further. I don't disagree with you. I mean, I
think we're getting there. I just think we're not
quite there yet, so in this particular case, I
think hepatocytes are going to cover more of your
bases, more of the signalling pathways, cofactors
that we just described, nuclear receptors,
alternative pathways and even working in synergy
all exist together in a human hepatocyte system
so--
DR. DERENDORF: Yes, I'd like to come back
to my previous comment. I'm a little uncomfortable
with that clean cut cutoff of 40 percent as a
threshold for significance or relevance,
particularly we need to define what we're
measuring. We need to define what is an
appropriate positive control. We need to define
what concentrations should we look at, what time
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point. And I think unless we do that and have a
correlation with, if it's really meaningful, that
40 percent seems arbitrary.
DR. LECLUYSE: Yes, and that's honestly
been the ongoing debate over the last, I would
argue, couple of years. And by the way, I think we
have defined all those other parameters that you've
mentioned, and now, it's just, and this is where
I'd like to open the floor for discussion, and I
think that's part of what the point is is how
comfortable are we with that 40 percent mark? I
think that's--I would argue that's where we need to
focus. I mean, there's other things that have been
brought up around hepatocytes and doing these in
vitro studies where I think is more away from the
point.
But I think those kinds of issues are
valid points that still need to be up for
discussion somewhat so--
DR. GIACOMINI: I think I just wanted to
echo what Paul said about the transporters not
really being in place in the hepatocytes. I don't
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know if this is still the best system, you know, to
test for inducing the nuclear receptors.
The other comment I had was we've tried
making constructs, you know, reporter constructs
and then transfecting them into hepatocytes. Have
you tried that kind of--so that you get a more
quantitative readout at the end of the, you know,
comparative quantitative readout?
DR. LECLUYSE: Right, yes, no, actually,
we do that, too. I mean, we basically, you know, I
should qualify this: my academic lab does
do--takes all those measures. In fact, you do get
normal disposition of human CAR using the primary
cell versus these, you know, the immortalized cell
lines, where CAR translocates constituitively to
the nucleus, as you're aware.
So, yes, certainly, you know, here again,
you're still using primary hepatocytes to get to
the answer. And I think the complementary tool
here, again, of following endogeneous gene
expression with your reporter assays is probably
even the best way to do those particular
310
assessments, I would advocate, so--
DR. STRONG: I think generally, at least
in our guidance, we do accept the fact, though,
that this issue of induction of 3A4, if we see
that's negative, that we probably don't have to
worry about C92C19. My concern, though, comes back
to the same issue that I think is really pertinent
today, and that is what's the way we define an
inducer and not inducer, the 40 percent?
In fact, what I did was one of the slides
that you showed with the comparison between 2B6 and
3A4 with the number of compounds, I looked at
phenytoin which is a strong CAR inducer, and
compared it to rifampin. When you do that, it
shows that the induction of 3A4 defined by the 40
percent rule, phenytoin is not an inducer.
And so, the question is what's going on
here? Well, I think it comes back again, and some
folks have alluded to it, is the hepatocyte
experiment and the hepatocytes themselves. I think
all of us agree that you can find hepatocytes that
have been induced to their maximum, and you see
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very little additional induction. And if you look
at the particular figure he showed, the basal
activity in that set of experiments with the 14
compounds, whatever they were, it was considerably
higher than what you saw, say, in the 2B6. So it
may be just experimental design.
And again, I think this is a question that
we have to really grapple with if we're going to
use hepatocytes for induction. Maybe we need to
define better some parameters with respect to the
hepatocytes we're using.
I wanted to make one other comment off the
subject, but I think it's great. I think again, we
believe that enzyme activity is still a gold
standard. On the other hand, Ed brought up the
issue of ritonavir, an inducer and inhibitor, and
how some of these other measurements like MR8 can
come in and add additional information.
Another way to look at that, though, is
that we're looking at mechanism-based inhibitors.
And in most of these drugs, when you're doing your
inhibitor study, you'll already know that your
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compound is or is not a mechanistically-based
inhibitor, so that you can put a red flag up with
regards to induction studies.
DR. VENITZ: Ed, I have two questions:
how do--your CYP induction, how does that compare
to UGT inductions? Have you looked at that at all?
DR. LECLUYSE: Yes, in fact, I don't know
if you got my background slides, but I did include
some UGT1A1 data in there, too, and basically, as
you may be aware, UGT1A1 is unusual in the sense
that it's regulated by all three receptors. And
so, activators of those three receptors will induce
UGT1A1 in human hepatocyte preparations, according
to the potency of the compound, and there, it's the
compound's ability to activate those nuclear
receptors.
So, you know, here again, you see the most
potent induction of UGT1A1 with things like
rifampin, phenobarbital, and also activators of the
AH receptor like 3-methylclanthrine, homeprizole.
DR. VENITZ: The second thing: can you
help predict hepatic enzyme induction for GI enzyme
313
induction, 3A4?
DR. LECLUYSE: Well, that's an interesting
point, because that's also a debated issue
currently right now, and the fact that the gut
enzymes are regulated by other factors that are
unique to the gut--now, bear in mind that the
profiles of these nuclear receptors are
tissue-specific, so you will find PXR, for example,
in the gut. And so, inducers of hepatic 3A or
activators of PXR will induce hepatic target genes
as well as the gut.
But there's other things going on in the
gut that are not operative in the liver and vice
versa, like with the vitamin D receptor, for
example. So there are additional mechanisms that
might be operative in the gut that may cause
upregulation of transporters of P450s that you
wouldn't observe in just an hepatocyte model, for
example, so--
DR. VENITZ: Any other questions or
comments?
[No response.]
314
DR. VENITZ: Then thank you again.
DR. LECLUYSE: Thank you.
DR. VENITZ: Shiew-Mei?
DR. HUANG: About the 40 percent, I just
wanted to throw this question out. Initially, we
got this from the PhRMA paper, although I know that
there is still discussion on whether this is too
high a value; should we be more conservative, 20,
25, or 30 percent. But I think the cut-off should
be supported by data, and as John mentioned that
based on some of the existing data, perhaps 40
percent is too high a cutoff.
And so, I was going to say in our concept
paper, we recommend the evaluation of 3A along with
2C9, 2C19, and we have not included 2B6 or UGT1A1,
although this will be some time to come. So I
thought perhaps it's important maybe we consider to
have different cutoffs depending on what
information we would like to get from 3A. If you
want the information of the certain cutoff to
support that, if 3A data is negative, then, we
don't have to do 2C9, 2C19. Perhaps 40 percent
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would be sufficient.
But if you're going to include 2B6 or
UGT1A1, then, perhaps there's a different cutoff.
And I'd like to see what your opinion, really,
because I think it's data-driven. We need to know
very carefully what data we have.
DR. LECLUYSE: Well, I can look at it from
a number of different perspectives, Shiew-Mei. And
I'd like to hear the panel's views on these, too,
because the one issue is, you know, just the views
on enzyme induction as an event in itself,
especially the clinical relevance of it as an
event. Now, I can tell you that I have my own
opinion on the chronic activation of these nuclear
receptors by not only drugs but any xenobiotic can
be an issue, especially the more potent ones, and
that you would want to stay away from those. But,
you know, that would be like the rifampin type
activators.
So the question is like where do you start
worrying about it, you know, where you're more in
the gray zone or where are you comfortable saying
316
that it's a negative result, which also can be
interpreted as a not significant enough of a result
is another way I look at it, because, you know--so
the assumption is if you've done everything else
right, and at the optimal concentration, your drug
or a particular drug never induces more than 40
percent of your positive control like a rifampin.
What's going to be the clinical outcome of that?
Is it really going to be noticed above and beyond,
you know, the normal distribution of the
population, et cetera, et cetera? I mean, we've
had these discussions before.
And so, you know, but that's different
than asking the question, does it have a potential
to cause an interaction, you know? And so, I think
that's where the debate really lies. And, you
know, I could argue both ends of the argument,
depending on how conservative you want to be. So,
you know, I think that's--I'd like to hear the
agency's view on that as well as the panel's view
on that so--
DR. SINGPURWALLA: I'm surprised that our
317
chairman on the matter of cut-off, our chairman has
not raised his pet issue, namely utilities. Is
there no discussion of utilities in these cut-off
points?
DR. VENITZ: He's not really dealing with
clinical yet. This is purely in vitro. The
utility has something to do with what happens if
this turns out to be clinically relevant.
DR. SINGPURWALLA: Factored in subsequent
to utilities.
DR. VENITZ: Yes.
DR. SADEE: I still have just a quick
comment that we haven't mentioned that, for
instance, CAR consists of multiple, multiple
isoforms, spliced isoforms. And so, that not only
changes between tissues but also between
individuals and the splices contain 14 different
proteins that are all differentially expressed,
too.
Do you consider this as a potentially
problematic factor, or is it a factor that could
account for the finding that sometimes, you find an
318
adoption, sometimes, not?
DR. LECLUYSE: Yes, I think that's an
excellent point. I mean, that's sort of where our
current understanding leads us to believe that
variability in things like the particular receptor
and differences in the cofactors that even regulate
these receptors all factor into some of these
interindividual differences. Bear in mind that
even with 3A4 or the difference between 3A activity
baseline that we brought up that you've got 3A5
contributing to the baseline activity that's not
really very inducible compared to 3A4.
So you've got all these things operative
in vivo, and that, here again, goes back to the
point that we raised again: while I like human
hepatocytes, and it's probably more indicative of
all these factors, now, I don't think we have a
complete understanding as to what the--whether
there's an individual subpopulation of individuals
that are going to be maybe on one extreme of the
spectrum or another.
Interestingly, as you may be aware, that
319
the known polymorphisms for these receptors suggest
that for PXR, anyway, that most of them don't
really have a functional relevance. Now, CAR, on
the other hand, seems to show a lot more
variability in a lot of different ways, including
the expression levels. It seems to be more
susceptible to shifts, ebbs and flows, you know, in
a person's social life, you know, genetic makeup,
et cetera, et cetera, whereas PXR, for whatever
reason, through evolution, it's pretty stable.
It's pretty amazing what we've been able to do to
try to vary PXR expression in human hepatocytes,
and you can imagine we've done everything that's
possible to vary its expression. It's fairly
stable. It's almost like a housekeeping gene, in
that sense.
Whereas, CAR can be variable. So, I mean,
I think--but the net results is over the course of
looking at three to four donors for the same drug
at the same concentrations, you know, we generally
get a good clue as to whether a compound is likely
to induce or not so--
320
DR. VENITZ: Okay; last question.
DR. JUSKO: It looks very promising that
this type of screen using human hepatocytes would
allow one to anticipate enzyme induction for
multiple CYPs. But this is partly based on the
premise found with rifampicin and anticonvulsants
that these drugs are a bit ubiquitous in inducing
many CYPs. Has the reverse type of literature
review been done to see how many drugs may induce
one CYP and not others? I notice in your list, you
have CLZ as an inducer of CYP3A4. Does it induce
the other CYPs?
How many sort of false negatives, or I'm
not sure which way it's going to go, how many
misleading results will there be because of the
lack of ubiquitousness of this kind of thing?
DR. LECLUYSE: Yes, well, actually, I was
hoping early in my academic career that that was
exactly the case. So then, we could get excited
about these unique kind of compounds that were very
selective or specific inducers. When I first
started my career, I hate to admit, again, that it
321
was over a decade ago. We kind of went into this
with this biased impression that there's, like, 1A
inducers, there's 2B inducers, there's 3A inducers,
suggesting that there's, you know, some distinction
between them.
And one of the first things I became
disappointed in is the fact that the human doesn't
seem to operate that way so much. In fact, for
whatever reason, the receptors have evolved to
where generally, if you have inducers of 3A, you
always see induction of 2C9. And same way with 2B.
I don't know why it is, but it seems to be the
case.
So we've been out there searching. I
honestly have been looking for compounds that will
just selectively induce particular subfamilies of
the human P450s and not come across--and a lot of
that data, admittedly, you know, partly due to time
but partly due to proprietary nature, et cetera,
you know, we've not come across over the, you know,
years and years we've been doing this of compounds
that are that selective.
322
And it kind of makes sense. I mean, you
know, the other thing I didn't get to do, and it's
part of my background slides, I actually have,
like, some of the promoter sequences for all the
promoters of the 2C promoters, 2B and 3A, and what
they share in common, and it begins to make sense
why they are coregulated and why it would be very
difficult to come up with a compound that
selectively induces any one of these, because on a
molecular level, it just wouldn't make sense that
it would happen, number one, because of the
overlapping specificity of the nuclear receptors
themselves and the fact that they share a lot of
commonality in their DNA binding domains.
So basically, they're meant to kind of
overlap and to crosstalk on these specific
isoforms, so--
DR. VENITZ: Okay; thank you again.
Our last presentation, right, for today,
is Dr. Reynolds. Kellie is in the Office of
Clinical Pharmacology and Biopharmaceutics, and she
is a team leader in Division Three.
323
DR. REYNOLDS: I just have a brief
presentation to open up a topic that's been
mentioned in two other talks today. It's a topic,
I think, that's been bounced around at several
other meetings, so we finally want to bring it to
the Committee for you to discuss.
The term that's used is multiple inhibitor
studies, and it really does refer to a lot more
than just multiple inhibitor studies. That's just
the terminology we've used. So I just want to
address what we're actually talking about, why we
think we need this information or may need this
information in some cases and how we might collect
the information.
So what we're actually referring to are
studies that are conducted to determine the effects
of a new molecular entity at the maximum exposure
that's likely in patients. And by effect, we mean
adverse effect.
And there's several different reasons we
might need this information. The primary reason is
to define the safety at the top of the exposure
324
response curve for adverse effects. And the
example that is brought up most often is for QT
prolongation. So this is actually mentioned in the
ICH draft document for the clinical evaluation of
QT prolongation, and there's also similar wording
in our draft concept paper for drug interactions.
So it mentions that if there aren't any
safety concerns, it may be useful to look at the
effect of the drug at substantial multiples of the
anticipated maximum therapeutic exposure, and if
you can't get to that exposure by giving higher
doses of the drug, you may do different types of
inhibition studies.
And another reason we may need this
information is to really just define what the worst
case scenario is for the drug. There are numerous
reasons that patients might be exposed to elevated
drug concentrations above what was observed in
clinical trials. It may be due to drug
interactions, genetic polymorphisms of the drug
metabolizing enzymes, renal impairment; it could be
hepatic impairment or multiple combinations of
325
these factors.
So there are several different ways that
we can get this information. We can give a higher
dose of the new molecular entity, if that's
possible. We can give the drug with a high dose of
a potent enzyme inhibitor. We can give multiple
inhibitors if the drug is metabolized by different
enzymes. If it's a drug that's metabolized by an
enzyme that has different genotypes, we can give it
with poor metabolizers to help higher
concentrations, or we can combine these factors,
and that's why these are called multiple inhibitor
studies. You may give the drug to patients with
renal impairment in combination with an enzyme
inhibitor, or you may give it to 2D6 poor
metabolizers in combination with a 3A4 inhibitor.
But there are some special considerations
for the studies. We need to consider what safety
data are available, both in animals and in humans.
Do the safety data actually support the conduct of
the studies? And we also need to consider the
relevance of the high exposure: what is the
326
expected dose in the clinic? Have higher doses
already been given? Did they start out looking at
a much higher dose and then settle on a lower dose?
What are the expected concomitant
medications? Is it likely that inhibitors will be
given with the drug? And that's an important
consideration. And also, what is the target
population?
So there's several steps in the process:
first, if you're going to do a multiple inhibitor
study, you need to know the effect of individual
factors by themselves first, and then, you can
simulate the effect of the multiple factors. And
if there are safety concerns, it's probably a good
idea to study lower doses first to see what the
actual fold increase in concentration is before you
actually give a higher dose with the potent
inhibitor. And so, it is multiple step process
that would take quite a bit of time.
And there are not a lot of examples. We
don't have a whole lot of data on this. And I
guess that's probably one of the concerns. But we
327
did find two examples. The first example is for
repaglinide, and this drug is a substrate for
CYP2CA and CYP3A4. And there was an interaction
study conducted in 12 healthy subjects. It was a
four-way crossover study. They received the
repaglinide either with placebo, itraconazole,
which is a 3A4 inhibitor; gemfibrozil, which is a
2C8 inhibitor; and also, the combination of
itraconazole and gemfibrozil.
And you can see that there was an increase
in the effect. When we gave it with itraconazole,
there was a 41 percent increase in the AUC. With
the gemfibrozil, there was a 712 percent increase.
And with itraconazole, it was almost a 20-fold,
with itraconazole plus gemfibrozil, both
inhibitors, it was almost a 20-fold increase in
concentrations.
Another example is telithromycin, and this
example is actually in the label. This drug is a
substrate for CYP3A4. Thirteen percent of the dose
is excreted unchanged in the urine, but that may
serve as a compensatory elimination pathway when
328
metabolic clearance is impaired. So if you give
ketoconazole with telithromycin, there is a 95
percent increase in the AUC, and in patients with
severe renal impairment, there's about a 90 percent
increase compared to normal, healthy volunteers.
And very limited data is just from two
subjects. But in two subjects with severe renal
impairment who are also given ketaconazole, the AUC
increased four to fivefold compared to normal
volunteers who did not receive ketaconazole.
So in summary, just to prepare for the
questions that we have, what we're referring to
here when we say multiple inhibitor studies is any
studies where we're trying to determine the effect
of the new molecular entity; its adverse effects at
the maximum exposure possible. And we think it may
be important in some cases to consider this,
because some patients may be exposed to the
worst-case scenario. We want to define what that
is and evaluate what happens there.
And the way we can evaluate it in some
cases, just a single factor will be enough to do
329
this. And in some cases, we may need multiple
factors. But there are a lot of different
unanswered questions that we need to consider for
this: first, how practical is the approach? It
does take a lot of different steps, and if you need
the answer at a certain point in drug development,
you need to get all the information prior to
conducting the study.
Are there certain cases where we think we
need this information and other places where it may
not be necessary? And do we actually have enough
information about the effect of multiple factors to
make a specific recommendation? I guess that's
kind of the same as are we smart enough? Do we
really know what we're doing here?
And there are just limited data. There's
probably one or two other examples that we have,
other than the two that I showed here. And is the
general recommendation acceptable, or do we need to
make it more specific? There are some general
recommendations in the ICH guidance and also in the
concept paper. Do we need to be more specific
330
about when we actually think we need to make the
recommendation?
And also, is there a possible role of
population pharmacokinetics for determining what
the effect of multiple factors would be? If we
actually enroll patients who have the multiple
factors on board into the clinical trials, with
appropriate population pharmacokinetics, we may be
able to determine what the effect is.
And so, there are going to be two
questions posed to the Committee regarding this:
first, is it acceptable to recommend this under
certain circumstances, and also, if we do recommend
this, what other issues should be considered first?
DR. VENITZ: Thank you, Kellie.
Any quick questions or comments?
As I said, we will discuss the individual
questions at the full discussion after the break.
Are there any quick comments or questions to the
presentation?
Steve?
DR. HALL: Could you clarify, is there
331
sort of an agenda that would lead you to include
this in this drug interaction guidance? It seems
to me that it's not truly in the spirit of the
overall document, that it's a separate issue. Is
there some reason that you believe it should be in
there?
DR. REYNOLDS: I think--well, one reason,
Shiew-Mei may be able to address it better, just
because it's been talked about a lot, and it seems
because it does involve drug interactions, and it
does involve specific study design concerns, that's
one reason it is in here. It is a little bit
different from the rest of the tone of the
document, though. If Shiew-Mei wants to provide
more insight--
DR. VENITZ: Jeff?
DR. BARRETT: You mentioned that on the
why was to define the worst case scenario. But
under what conditions would you say you need to
define the worst-case scenario? What properties of
a drug would lead you to say that I need to know
that?
332
DR. REYNOLDS: I think it really would
depend on what we know about the safety of the
drug. I mean, if we feel like there are situations
where patients may be exposed to higher
concentrations than they were exposed to in the
clinical trials, and we have special concerns about
the drug, then, maybe one situation. It would
depend on, like, in phase two, what the dose
finding was, whether they actually ended up
settling on the highest dose they looked at or
whether they actually looked at doses several fold
lower and settled on one of the lower doses.
DR. VENITZ: Larry?
DR. LESKO: Yes, just in the context of
Kellie's presentation, the adverse event that comes
up often and is spoken about in this context is QTC
prolongation. Now, the question would be what else
is there beyond that that would be sort of a
characteristic of this concern about multiple
inhibition? I don't think it would be dry mouth,
for example, or things of that sort, of course.
So we have to sort of think about when is
333
this concern a legitimate concern. And one thing
that wasn't mentioned is how we ought to be
thinking about the exposure-response relationship
that we do know about prior to making the decision
on these multiple inhibitors, and how does that
factor into the decision? That is to say, how can
modeling and simulation play a role here based on
an analysis of the data that's contained within the
clinical trial program, to look at worst case
scenario and simulate its settings as a
prerequisite to doing something live.
DR. VENITZ: Any other questions or
comments?
Paul?
DR. WATKINS: Being responsive to the
ethical concerns of putting together combinations
of drugs or medical conditions like renal failure
with another inhibitor, would this be proposed
during drug development as--I'm just curious--as
this is something you have to do to establish
safety in patients that may be out there, or would
be you either have to fess up and put in bold,
334
black letters that ketaconazole shouldn't be given
with this drug in people with renal failure based
on what we know, unless the company is willing to
do this study to see if that could be removed from
the label or both?
DR. REYNOLDS: We're certainly not to the
point yet where we're saying you have to do that.
We haven't said that to anyone, as far as I know.
And as far as whether or not there may be
situations where there need to be special warnings
in the label, I think that's going to be very
drug-specific.
DR. WATKINS: Because my interpretation is
that Merck was being asked to do something that
they felt they couldn't do, not that this was
something that you wanted to do and couldn't do.
DR. GOTTESDIENER: Could I respond to
that? The answer is Merck has not yet been asked
to do that for a specific compound. There are
other members of industry who have told me that
they have been asked to do that, specifically in
relationship to a QTC study, or at least it's been
335
proposed.
In at least the one case I know the
details of, the company was able to convince the
agency that in the end, it really didn't make a lot
of sense, because again, this is anecdotal, so I'm
not sure I'm capturing everything, but the idea was
that the particular risk of QTC effects for that
particular drug appeared a little more remote than
most, and I think in fact, the agency must have
made a decision that in this particular case, the
risk-benefit of going to those high doses didn't
quite exist.
I do think that the issue of, though, how
high you're going to go in the QTC studies is
something that every company faces every day, and I
think as mentioned, there are many ways to get
those kind of margins overall. But it's clear that
there are situations where without these kinds of
what I still call extraordinary efforts, it may or
may not be possible to do so, and then, I think the
question is what are--as Dr. Lesko said, what is it
you're worried about, and how concerning is that
336
issue overall?
I think Merck, as well as other companies,
would say that if there were a very specific issue
that needed to be addressed to use a drug safely,
such an approach might very well make sense. But I
personally believe that those examples are very far
and in between.
DR. VENITZ: Anything else?
[No response.]
DR. VENITZ: Okay; then, let's take our
last break for today. We'll reconvene at 4:00, and
the Committee will discuss the 11 questions put in
front of us.
[Recess.]
DR. VENITZ: All right; our final task for
today is to work through 11 questions that Dr.
Huang has put in front of us. And the way I'd like
to manage that, I'd like for Shiew-Mei to introduce
each question with help of at least one of our
Committee members, and then, have a brief
discussion before we vote. And just like we did
this morning, I'm going to have to go around the
337
table, make a voice--collect voice votes and then
tabulate them.
So, Shiew-Mei, go ahead.
DR. HUANG: All right; thanks, Jurgen.
Our first question: the next few
questions will be related to inhibition of CYP
enzymes and transporters, so the first question is
related to inhibition of CYP enzymes.
So based on what we have said in the
concept paper, we say five major CYPs are important
to evaluate for inhibition. So if a new molecular
entity is not an inhibitor of the five major CYPs,
based on in vitro data, then, there is no need to
conduct in vivo interaction studies based on these
CYPs.
DR. HALL: So could you define "not"?
[Laughter.]
DR. HUANG: I mean, one approach is to use
the I over KI ratio, and the other one is to use
the rank order. The approach I have mentioned, we
do not say it very clearly on. We didn't
specifically say if I over KI ratio is 0.1, then,
338
there is no need to inhibit, although we did
mention if the ratio is 0.02, you definitely do not
need to evaluate. And further, we have talked
about using a rank order. If a more potent or
smaller KI were used, you don't see any inhibition
in vivo, then, you do not have to do the others.
DR. HALL: But the rank order, you have to
do a study in vivo, right, based on the rank order
approach so--
DR. HUANG: Right, so if we use our
definition, we could vote; you could answer a
question based on our ratio, I over KI, of 0.02, or
you can--at 0.1. So maybe when you answer, you can
say yes for 0.1, no for 0.02 if we come down to
that it's a critical issue. That would be very
helpful for us also.
DR. VENITZ: So we do allow yes buts? Is
that what you're saying?
DR. HUANG: No, I'm saying since Steve,
Dr. Hall, has asked me to define what in vitro
data, and we always look at I over KI, and I we
have defined as CMAX at steady state at a highest
339
dose, projected CMAX, and it's a total
concentration, not free concentration, versus KI.
So sometimes, we use IC50 when KI is not available.
And so, currently, it could be interpreted
that we set in our concept paper a ratio of 0.02 or
lower. We would not need a study. And I think Dr.
Hall is bringing up another issue. Perhaps that
number is too conservative. Maybe we should look
at 0.1. So I would recommend that you could amend
your answer to say I would say yes if the ratio is
0.02. But it's better if it's 0.1.
DR. SADEE: So, let me clarify. I'm not
quite sure. Then, there's no need to conduct in
vivo interaction studies. Does that also include,
well, PGP or--
DR. HUANG: No, just CYP interaction
studies.
DR. SADEE: So if we know about a compound
that is metabolized by these enzymes, but we--we
would have to know that there's no other possible--
DR. HUANG: Here, we're talking about--the
guidance talks about the effects of a new molecular
340
entity on others; also, others on this enzyme. And
right now, we're talking about the effect of this
new molecular entity on others.
DR. SADEE: Okay.
DR. CAPPARELLI: Just a clarification of
downstream from that, making the answer no. If I
recall, there's pathways, then, though, to screen
in population approaches or potentially other
modalities rather than a straight, you know, in
vivo study of a specific substrate.
DR. HUANG: Yes, I'd like to clarify.
This is only one approach. So you could use
population kinetics or other specific studies to
say there is no interaction. But I'm saying we
could extrapolate from in vitro when using I over
KI ratio. When there is no inhibition, then, we do
not have to do a study in vivo.
One of the comments that I've heard from
outside FDA is that the drug may affect
transporters, and that indirectly affects
metabolism. And so, that's one of the reason there
is some suggestion that even though it shows a drug
341
may not affect this CYP enzyme, but if through
affecting transporters, they may still affect the
CYP enzymes. So that's one of the reasons
everyone's throwing the question.
DR. VENITZ: So how do I vote if I believe
that in vitro trumps in vivo? In other words, if I
have evidence in vitro that there is no inhibition,
that there is no necessity for an in vivo study,
how should I vote? Because I think that's what
most of us agree with, but I'm not sure how to
vote.
DR. HUANG: Well, you're saying most
people agree?
DR. VENITZ: No, I'm saying I'm not sure
how I can vote on your question, but I know what I
believe: I believe that if you have in vitro
evidence that there is no inhibition, that there
shouldn't be any necessity or any need to do an in
vivo study.
DR. HUANG: Right, for inhibition, yes.
DR. VENITZ: If that's what I believe, how
should I vote on this question?
342
DR. HUANG: Yes.
DR. VENITZ: Okay.
DR. SADEE: But I think you have to add
there, there's no need to conduct in vivo
interaction studies based on these CYPs targeting
only these CYPs.
DR. VENITZ: That's what it says.
DR. SADEE: Okay; well, if it's clear--
DR. VENITZ: Okay; so everybody then
understands the question.
Okay; then, let me randomize the way we
vote, because I was advised by our statistician
that I was biasing the Committee.
[Laughter.]
DR. VENITZ: So let's start with Dr.
Watkins.
DR. WATKINS: I agree with that statement
as a general statement. I could think of specific
instances where even if you didn't show inhibition,
it might be prudent to do an in vivo interaction
study. And the other thing is just to emphasize
that the devil is in the details. For instance,
343
we've talked about, Shiew-Mei, it's standard, I
believe, within industry to use two different
substrates for 3A4 and in vitro studies, a big one,
a little one, reflecting the fact that it can act
like two different enzymes.
And since that survived through the Basil
consensus and the PhRMA document, there would have
to be new data, I would think, to take it out of
the FDA's guidance now, which then leads to the
problem what do you do with that information if one
substrate group inhibits and one doesn't?
I mean, those sorts of details, I think,
will come back as industry response. But as a
general statement, yes.
DR. VENITZ: Dr. Sadee?
DR. SADEE: I think I agree with it with
some hesitation, you know, that it doesn't state
that you don't need to do in vivo interaction
studies. It's just that you don't need to do it
for that reason. So if I understand that
correctly, my answer is yes.
DR. VENITZ: Dr. McLeod?
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DR. MCLEOD: Yes.
DR. VENITZ: Dr. Jusko?
DR. JUSKO: Yes.
DR. VENITZ: Dr. Hall?
DR. HALL: Yes.
DR. VENITZ: Dr. Giacomini?
DR. GIACOMINI: Yes.
DR. VENITZ: Dr. Derendorf?
DR. DERENDORF: Yes.
DR. VENITZ: Dr. Davidian?
DR. DAVIDIAN: I'll abstain as a
statistician here who doesn't have the expertise to
judge.
DR. VENITZ: Okay; fair.
Dr. D'Argenio?
DR. D'ARGENIO: Yes.
DR. VENITZ: Dr. Capparelli?
DR. CAPPARELLI: Yes.
DR. VENITZ: Dr. Blaschke?
DR. BLASCHKE: Yes.
DR. VENITZ: Dr. Barrett?
DR. BARRETT: Yes.
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DR. VENITZ: And I would add my yes, but I
don't--
[Laughter.]
DR. VENITZ: --I don't like the way you
define absence of inhibition in vitro. 0.02 to me
is too conservative.
DR. HUANG: Okay; before I go to the next
question, I just want to clarify: in our concept
paper, we did recommend to use two different CYP3A
substrates, and if either of them shows positive,
then, this, then, you would need to do an in vivo
study.
The next three questions are related to
PGP transporter, and this was a very statement from
the April discussion of this Committee that if a
new molecular entity is an inhibitor of PGP in
vitro, then, there is a need to conduct an in vivo
study using digoxin or other suitable substrates.
DR. VENITZ: Okay, any discussion?
DR. DERENDORF: I think we have to define
is.
[Laughter.]
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DR. GIACOMINI: Shiew-Mei, are we going to
use the same I over KI in the same way, in the same
spirit that we do?
DR. HUANG: Well, for the PGP, what we
have seen, at least, in the submissions is you use
the in vitro system such as CAPO2 or other system
where you look at A to B--or, I'm sorry, this is an
inhibitor, so you'd look at the effect on digoxin,
a labeled digoxin transport, and when there is an
effect, which we do not define, but you could look
at, such as quinidine effect, as a positive
control.
I mean, we did not specify the detail in
this guidance, but if the Committee thinks it will
help to have a detailed appendix just like we have
for the CYP enzyme, we could do that. We have not
done it, because as we have heard earlier, there
are different ways of conducting it. There's not a
standardized way, although based on the digoxin
study, we often can conclude that this drug is an
inhibitor of PGP, based on its effects on digoxin
or other substrates transport.
347
DR. DERENDORF: But you need some
quantitative cutoff here, some quantitative cutoff
to make that decision whether it is or it is not.
So what would that be?
DR. HUANG: Okay; we have not specifically
stated, but usually, when we have this submission,
it will say this is an inhibitor, based on either a
statistically pure t-test. I mean, that's what we
have seen in the submission, to show there is a
difference in the transport, A to B, B to A for the
digoxin or compared to a quinidine effect, and it's
comparable, or maybe a certain percentage of it.
DR. DERENDORF: But that wouldn't really
be consistent with the first approach, because
there, we standardize it to the I, to the
concentration that we have, so I think we need to
do that as well.
DR. HUANG: Okay.
DR. GIACOMINI: I mean at least be
measuring in the therapeutic range, you know,
somewhere in the therapeutic range and then look at
the inhibition then.
348
DR. HUANG: I'm sorry; for some reason
standing here, it's hard to hear.
DR. GIACOMINI: So I'm just saying, I'm
just agreeing with Hartmut that in fact, it's good
to at least standardize that in some way. So I
like your idea of comparing, having a comparison
with quinidine and dig, that comparison, but I also
like the idea of, you know, making sure you're in
the therapeutic range, where you're seeing an
inhibition in and around this. I kind of like I
over KI as being just sort of a guidance.
DR. HUANG: Okay; so, should I amend the
question so that it would be similar to the first
one, that we are going to recommend something on in
vitro data? We probably will use I over KI, the
ratio, and suggest, say, for example, with--this is
what you see, and compare to a standard. Then,
based on that, we'll come to this question.
So I guess the recommendation is we have
something in our concept paper, in the guidance.
DR. HALL: I think staying away from the
phrase therapeutic range would be good, because at
349
this point, they have no idea what the therapeutic
range would be at this point in the history of the
drug, right?
DR. WATKINS: The other part of that is
the choice of probe, and I think if you say digoxin
or other suitable substrate, everyone will do
digoxin until there are other suitable substrates
in the document. And, you know, it's a dilemma,
because digoxin may be the best substrate, but we
know it's transported by other transporters.
Furthermore, you give, you know, a tenth
of a milligram, and it all gets in. So it gets by
an absorption MDR-1 gene product, p-glycoprotein.
So there's some intuitive disconnect about using a
digoxin, and you're clearly not evaluating the
intestinal component, and whether something else
like fexofenadine would be better; you know,
unfortunately, we still don't know the answers to
it, and that's the reservation that I have at this
stage about recommending, you know, an in vitro-in
vivo algorithm. But I don't know the alternative;
I don't know what else to do.
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DR. VENITZ: And that's exactly the reason
I'm going to vote against this question. I don't
think the science is there yet. I don't think we
know necessarily which in vitro transporter--not
transporter but probe substance to use. I'm not
sure whether digoxin is the most informative
clinical substrate, so maybe in a couple of years,
we'll know that. Right now, I don't think we can
make the same jump that we make in terms of your
question one.
DR. HUANG: Yes, in the current
submissions, we have seen studies done with digoxin
and fexofenadine.
DR. GIACOMINI: Can I comment on that
also, on the digoxin?
DR. VENITZ: Absolutely.
DR. GIACOMINI: I mean, digoxin, there's
multiple lines of evidence, certainly, that it's a
PGP substrate: cell culture, knockout mouse;
there's a quinidine interaction that's gone
through--in my mind, it goes through sort of all of
the tiers in terms of levels of evidence in terms
351
of whether it is, it's not metabolized, so it's an
ideal substrate to use, and then, the specific
inhibitors, even if they have studies of the
drug-drug interaction in a knockout mouse, which
they're looking at quinidine-dig interaction, and
the quinidine-dig interaction doesn't occur in the
knockout mouse, and it does occur in the wild-type
mouse.
So that, again, suggests that that
particular interaction is pretty--
DR. VENITZ: I don't doubt that digoxin is
an in vitro and in vivo PGP substrate.
DR. GIACOMINI: Okay.
DR. VENITZ: It's just that the main thing
that we're concerned about is PGP as it relates to
drug absorption, and I don't think that's where the
major--where digoxin has a problem. Digoxin has a
variability of 70 to 90 percent.
DR. GIACOMINI: Right, right.
DR. VENITZ: So I don't think that's the
best in vivo substrate to find out whether some in
vitro inhibitor is actually going to change
352
protease inhibitor absorption. That's my concern.
DR. GIACOMINI: Okay.
DR. VENITZ: So I'm not doubting that
digoxin is a PGP substrate, but I don't think we're
testing for absorption interactions, which are the
ones that I'm personally most concerned about.
DR. GIACOMINI: But then, in the absence
of that, I mean, if you don't put something in the
guidance, then, even a dig study isn't even done at
this point, because this is a recommendation to say
that we need a clinical study. If you've got a PGP
substrate inhibitor, your enemy is that PGP
inhibitor.
Should you carry out a clinical study with
digoxin--
DR. VENITZ: Maybe in a couple of years,
we'll find fexofenadine or some other model
substrate is a better one. Maybe we'll find better
ways of assessing the in vitro potential to
interact.
DR. BARRETT: I think the original
intention of this was to be purposely vague so that
353
you would have a little bit of freedom to define it
as you saw fit. So, you know, even though the
original comment was to standardize between the
first two questions, it may be written okay as far
as the spirit of being able to recommend, assuming
the sponsor has done some studies here, not to do
an in vivo study, assuming they have some
compelling data on the in vitro side.
DR. SADEE: Your concern may be mostly
related to bioavailability, but this also relates
to other endpoints, such as do you get your drugs
into lymphocytes in HIV patients, and that may be a
very large effect. You cannot assess this with
pharmacokinetics necessarily.
So is that--you're only talking here about
an in vivo study that includes measurement of drug
levels in plasma and area under the curve; is that
correct?
DR. HUANG: Yes.
DR. SADEE: And if you have that, say, you
know certain target tissues, you would not
necessarily consider that--
354
DR. HUANG: Right, right, and just to
remind the committee that there is some
recommendation from the April meeting that digoxin
even is not the perfect substrate for PGP for all
the reasons we just heard, because of the clinical
significance on the change in digoxin, and that
was, at that time, digoxin was proposed as one
substrate to consider if the drug is a PGP
inhibitor. I know not everyone from that committee
was here today, are here today.
DR. VENITZ: Okay; any other comments,
questions?
Then, let's go the opposite way. So, Dr.
Barrett, you go first this time.
DR. BARRETT: Yes.
DR. VENITZ: Okay; Dr. Blaschke?
DR. BLASCHKE: Yes.
DR. VENITZ: Dr. Capparelli? Oops; sorry.
DR. CAPPARELLI: Took my spot.
DR. VENITZ: I'm going alphabetically
according to the seating order.
DR. BLASCHKE: My answer is yes, but I
355
would also just comment that I think that there's
been a couple of important points made, and that if
a drug is a PGP inhibitor, there may be a lot of
other kinds of clinical studies that might fall out
of that, as was suggested, perhaps those that
affect drug transport into cells, et cetera. But I
think this is an appropriate place to start.
DR. VENITZ: Dr. D'Argenio?
DR. D'ARGENIO: Abstain.
DR. VENITZ: Dr. Davidian?
DR. DAVIDIAN: Abstain.
DR. VENITZ: Dr. Watkins?
DR. WATKINS: Yes, if it is further
quantified what degree of inhibition and at what
concentration.
DR. VENITZ: Dr. Giacomini?
DR. GIACOMINI: Yes.
DR. VENITZ: Dr. Hall?
DR. HALL: Yes.
DR. VENITZ: Dr. Jusko?
DR. JUSKO: No.
DR. VENITZ: Dr. McLeod?
356
DR. MCLEOD: Yes.
DR. VENITZ: Dr. Sadee?
DR. SADEE: Abstain.
DR. VENITZ: Dr. Watkins?
DR. WATKINS: Yes, and just to comment, I
was glad Shiew-Mei clarified that, because I
remember when the first guidances were put
together, the point was made that the FDA has to be
concerned about safety and should not be dictating
science, and in that sense, digoxin is a very
relevant interaction. A lot of people on it;
neurotherapeutic index. And so, it's a reasonable
substrate from that aspect, although
scientifically, it's not perfect, so yes.
DR. VENITZ: All right; and my last vote
is a no, which according to my count, gets us two
noes, three abstains and eight yeses.
Okay.
DR. HUANG: Yes; the next question is
about a new molecular entity as a substrate for
PGP, and I need to clarify this here. When we have
the concept, when we have the guidance, we would
357
talk about how do you determine as a substrate, and
this would be one of the ways is to look at one of
cell systems and look at A to B, B to A, base
lateral to applicable transport and look at the
difference between these two.
And so, if you determine it to be a
substrate in vitro, and actually, the next two
questions are related: number one is to consider
the CYP3A status in making the recommendation, and
then, number two, the question is whether it's
proper to evaluate PGP-based interaction when the
new molecular entity is a substrate. So they could
be commented together. And when you say yes and
no, I think it's probably more informative to also
discuss the examples we used here, whether these
are appropriate examples to give.
DR. VENITZ: Any comments?
DR. GIACOMINI: Yes, so, in terms of three
and four, when you conduct a clinical study, what
we would be interested in at that point when a
clinical study is conducted is since this is the
substrate is what the inhibitor is, what inhibitor
358
to use in a clinical study. And since, of course,
this is one of those cases where we're going to
have to use an inhibitor that's going to be an
inhibitor, probably, of a transporter and an
enzyme, PGP and CYP3A4, for example, something like
that; so I guess I want to say that from my point
of view, three and four are hard to pull apart, you
know, because I don't see that I could pick an
inhibitor for three that didn't work for four. So
I would lump the two together, whether your NME is
a substrate of PGP alone or whether it is a
substrate of PGP and a CYP 3 and 4.
DR. HUANG: One of the reasons I did that,
because if this drug is a substrate of 3A, when we
assess interaction, we would recommend to use a
strong inhibitor.
DR. GIACOMINI: Okay.
DR. HUANG: The inhibitor that we
recommend in question three, four, they're not
strong 3 inhibitors.
DR. GIACOMINI: Okay; okay.
DR. HALL: So I guess it again comes down
359
to the details of whether such--whether there are
such inhibitors that can be used in some sense
ethically in these types of studies, and, you know,
ritonavir, for sure, there are concerns with it.
We've heard cyclosporin, verapamil, there are
concerns with those that the IRBs commonly express,
and so, in practice, I think there are some issues
with this.
I think, you know, the general principle
of the question, I don't think people would
disagree with. But whether you can execute that on
a large scale is another issue. And I'm not
convinced that these are reasonable choices of
inhibitors to be used for these types of questions.
DR. HUANG: Yes, one standard for us to be
putting on something the guidance to make a
recommendation is we have to have something that is
a general inhibitor that we will agree to, and it
can be used in a study. So if none of these are
practical inhibitors, then, we probably would not
be able to put that in the guidance or
recommendation.
360
DR. VENITZ: And that means we should vote
no, right?
DR. HUANG: If we couldn't think of any,
or we could put in a general statement instead of
putting the examples if these are not--well, one
question is we have to agree that when we found
that a drug is a substrate, then, we would
routinely conduct a study in vivo. That was one of
the important questions.
DR. VENITZ: Any other comments?
Go ahead, Terry.
DR. BLASCHKE: Well, just a comment about
the ritonavir. I think single dose ritonavir,
Steve, would not be a concern; certainly not a
multiple dose study with ritonavir, but certainly,
I think a single dose study with ritonavir would
not be a safety concern.
DR. HALL: Would that work, though, to get
the full interactive effect of ritonavir?
DR. BLASCHKE: We've done single-dose
studies with ritonavir looking at interactions, and
it's certainly a potent inhibitor even with a
361
single 400-milligram dose, yes.
DR. CAPPARELLI: But there still is a
specificity issue with ritonavir. In terms of
depending on the compound that you're looking at,
it's not just 3A and PGP, so you still have those
issues of what's, you know, how do you apply the
results that you get.
DR. WATKINS: Can I--yes, just I realized
it was helpful to me to think about, you know, why
we're being asked these questions. So with
digoxin, you know have a PGP inhibitor. You go to
a digoxin study. If it's a negative interaction
study, unfortunately, it doesn't mean you won't
inhibit PGP in the intestine and other things. But
here, I think the implication is if you have a
substrate for both PGP and 3A4, and you don't have
an interaction with ritonavir, you can stop. There
are no more rocks to turn over. That's the end of
the drug interaction considerations.
And I actually agree with that. But I
think that's the question. And then, the next
thing is if it's a PGP substrate but not 3A4, of
362
course, you could do ritonavir again. But being a
little more specific, again, sticking with
clinically relevant interactions, you do the
cyclosporin study. If that's negative; you're
done. You don't have to do anything else. And I
think I agree with that, too.
DR. HUANG: Yes, one of the reasons we put
in cyclosporin here for discussion, because it
affects a lot of transporters, not just PGP. And
so, as you said, if you do a study, and it's
negative, it's a very good information.
DR. WATKINS: With a positive control,
obviously. You've got some other probe; you're
showing that cyclosporin got in the right place in
the right concentrations, et cetera, but--
DR. HUANG: Right, right.
DR. VENITZ: So is this question, then,
supposed to read if the NME is not a substrate for
PGP and not a substrate for 3A4, no clinical study
will have to be done? Because I think that's what
I heard you say, Paul, right?
DR. WATKINS: Yes, I think we already
363
decided that, didn't we? I mean--oh, I guess no,
we didn't. You're right, no, no, we didn't decide
that.
DR. VENITZ: We talked about inhibitors;
we didn't talk about substrates.
DR. WATKINS: That's true.
DR. VENITZ: So are we here saying if the
in vitro is negative, stop; no further clinical
study? Are we saying if the in vitro is positive,
a clinical study has to be conducted? Because
that's the way I read this question.
DR. HUANG: Right, but Paul was going one
step further: if it's a substrate, and you did a
study with a cyclosporin or ritonavir, then, you're
pretty confident that other future transporter
inhibitors will not have an effect. It's just
cyclosporin and ritonavir inhibits a lot of
pathways, not just PGP.
DR. WATKINS: In other words, it doesn't
matter that it's not specific; it's just the
maximum way to knock out those two pathways. And
if that has no effect, and the study is done right,
364
you're done. You don't have to do anything else.
DR. BARRETT: Shiew-Mei, it strikes me
when I look at the questions that there's a
decision tree that's going to fall out of this,
assuming that the yeses and noes fall in the right
path. And if you could superimpose history on top
of what you're going to come up with at the end of
this, is there some idea of the sensitivity and
specificity of what that kind of a proposal would
look like, or can you do a kind of scenario testing
to this? I mean, you have the benefit of looking
back on a lot of development programs that have
made it to market.
So if you look at the decision tree based
on, you know, taking away those kinds of studies,
you know, would you arrive at the right--where you
think you want to be, I guess, with this kind of a
guidance?
DR. HUANG: I think this will be the
beginning of gathering some information. I don't
think we are at the stage yet that once you did a
study, if it's a positive, what else do you need to
365
do? I mean, with the cyclosporin study, if it's a
positive, you probably will report this in the
labeling. If it's negative, you could say a lot of
things that it does not affect, and probably, the
other PGP inhibitors will not be able to--
DR. BARRETT: You know, I know you're
laying this out prospectively. This is something
we want to put forward as, you know, moving
forward, but if you applied this kind of an
approach back to historical agents, where you had
the benefit of in vitro signals and in vivo
studies, you know, I just wonder where you think we
would end up. Do you have that kind of
information, or has the working group looked at any
of that?
DR. HUANG: We started to construct a
decision tree based on in vitro and how that
compares with digoxin; then, we decide whether to
do an in vivo. But once we reach an in vivo, we
haven't had enough information to say what to do.
For CYP3A inhibition, it's very easy. We
say if there's no interaction with medazolam, you
366
stop. If it does, then, you continue with other
sub, like, sensitive substrates or other
coadministered drugs. And we do have that layout
in our good review practices.
For PGP, we don't have that, partly
because many of the inhibitors that we're talking
about are not specific for just PGP, but I would be
happy to have any input from the Committee members.
DR. VENITZ: Are we ready to vote?
Go ahead.
DR. JUSKO: When I look back at your
slides and look at the severity of the
interactions, the first question we examined looked
at digoxin AUCs and the presence of quinidine, and
there's a 2.5-fold increase in AUC. So it's a
moderate interaction. The ritonavir interaction is
extremely strong, a 50-fold change, it looks like
to me.
But for question four, the single
interaction, it goes back to about a 2.5-fold, so
some consideration needs to be made upon what we're
going to learn and how important these interactions
367
are, and it looks like number three there is a very
important one; but going back to number two and
number four, they're not quite so important that we
need to do these clinical studies.
DR. HUANG: When you say number two,
number four, you mean the questions?
DR. JUSKO: The degree of interaction
demonstrated in previous studies in relation to the
benefit gained from doing these kinds of studies.
DR. HUANG: Okay; as mentioned earlier,
digoxin, because it's a high bioavailability and
others, so the extent of interaction may not be as
great. But we know for digoxin, 2.5-fold increase
is definitely important. And so far, since it's
probably the best substrate that we have as far as
PGP specificity is concerned and also the clinical
significance that the change in digoxin is
important; that's why we recommended it.
But if you're talking about the drug as a
PGP substrate, then, we don't know yet. Perhaps
the ritonavir and cyclosporin will have a very high
degree of interaction, cyclosporin and rosuvistat,
368
and that's one other transporter, has sevenfold
increase. So it depends on the substrate that
we're talking about right now. We're talking about
the new molecular entity as a substrate, so
depending on its kinetic or disposition
characteristic, you probably will have much higher
extent of interaction compared to digoxin.
I use digoxin just because it's what we
have. If you look at fexofenadine or others, those
are nonpure PGP substrates. You might see a
different extent of interaction.
DR. VENITZ: That's exactly the problem I
have with both of those questions. I don't know
anything about the NME. I don't know anything
about the degree of absorption. If it's 90 percent
absorbed, PGP, it's probably not particularly
important.
DR. HUANG: But we did see--we don't know
the mechanism of interaction, but we know about
ritonavir--
DR. VENITZ: I understand.
DR. HUANG: But for ritonavir and
369
vardenafil, we have 50-fold increase. Cyclosporin
and rosuvistat, we have sevenfold. So we're seeing
a great degree of interaction, possibly because of
some transporters.
DR. VENITZ: But you don't know whether
it's based on the fact that they're PGP substrates
is my point, so you're using some in vitro tests
that may have nothing to do with the interaction
that you're going to find when you look at
ritonavir interaction.
DR. HUANG: If they're a substrate of PGP,
we know ritonavir and cyclosporin, they do inhibit.
DR. VENITZ: Right, but it could be that
by giving ritonavir, something else is going on.
They did it in--
DR. HUANG: Correct.
DR. VENITZ: Okay; the second question or
concern that I have, what is the exposure response,
and what's the side effects or the negative utility
that--what are the stakes, basically? I mean,
here, you're not looking at the effect of the drug
on something else but of something else on the
370
drug.
DR. HUANG: Correct.
DR. VENITZ: So unless you know that, I'm
not sure whether you can give it a clear-cut yes or
no answer.
DR. HUANG: Right; we definitely put that
into consideration when we interpret a drug
interaction. For a drug that's a substrate of 3A,
we don't ask what is the exposure response before
we recommend an interaction study. We want to look
at interaction, what is the maximum effect of
interaction, and then, see whether they're within
that exposure response or not. And we don't say
that this drug has a very wide therapeutic range;
therefore, you do not need to study an interaction.
DR. VENITZ: But I think we know more
about 3A-4 interactions than we knew about PGP
interactions.
DR. HUANG: Okay.
DR. VENITZ: That's my--
DR. HUANG: All right.
DR. VENITZ: Any other--
371
DR. CAPPARELLI: I still have a question
on the yield on number three, and, you know, if you
really look at 3A substrates, are you really going
to catch anything extra by doing a ritonavir
interaction study? In other words, are there
examples where doing these interaction studies
surprises you and shows you no interaction?
Because the single dose PK is not going to reflect
what's going to happen in any clinical situation;
in other words, it will show you sort of the
maximal effect of wiping out a lot of systems, but
it's not going to tell you--you know, I'm wondering
if it's going to tell you enough to really justify
that study versus doing something more specific and
moving on from there.
DR. HUANG: Right. But doing a single
dose study might be able to tell us whether there's
a pharmacokinetic interaction, and we may not be
able to assess a dynamic or other additional
response. We know that.
DR. VENITZ: Okay; are we ready for a
vote?
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Then, let's start with Dr. Watkins:
question number three.
DR. WATKINS: Yes; do them one at a time,
or should I do four with that?
DR. VENITZ: Do both of them.
DR. WATKINS: I would say yes to both, and
the only suggestion I would have, and I understand
the problem probably with doing it, is having been
involved with certain drug approvals, often, the
interpretation of guidelines differs not only from
company to company but even within the agency.
So I would suggest rewording. It says
that you should do this. I would say that if you
do this, and it's negative, you don't have to do
anything else; I mean, just to clarify what I think
is really the essence of the message that will get
upper management and pharmaceutical companies very
excited about the work they don't have to do.
DR. VENITZ: Okay; Dr. Sadee?
DR. SADEE: So, what am I voting for?
DR. VENITZ: Three and four.
DR. SADEE: Well, as it stands, on three,
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I have to abstain, and four, I say no.
DR. VENITZ: Okay; Dr. McLeod?
DR. MCLEOD: Three yes, four no.
DR. VENITZ: Dr. Jusko?
DR. JUSKO: Three yes, four no.
DR. VENITZ: Dr. Hall?
DR. HALL: Three yes, four yes.
DR. VENITZ: Dr. Giacomini?
DR. GIACOMINI: Three yes, four yes, and I
like Paul's suggestion.
DR. VENITZ: Okay; Dr. Derendorf?
DR. DERENDORF: Three yes, four yes.
DR. VENITZ: Dr. Davidian?
DR. DAVIDIAN: Abstain and abstain.
DR. VENITZ: Dr. D'Argenio?
DR. D'ARGENIO: Abstain to both.
DR. VENITZ: Dr. Capparelli?
DR. CAPPARELLI: Three no and four no.
DR. VENITZ: Dr. Blaschke?
DR. BLASCHKE: Three yes and four yes as
amended by Paul.
DR. VENITZ: Dr. Barrett?
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DR. BARRETT: Three no, four no.
DR. VENITZ: And I have no on three and no
on four. So we've got seven on question number
three; we've got seven, yes; four, no; two abstain.
Is that right? On question number four, six yes;
five no; and two abstain.
Okay.
DR. HUANG: This question is trickier,
because right now, we say for inhibition
interactions, focus on the five major CYPs and
their emerging data on the importance of CYP2B6,
2CA, UGT1A1 and possibly other drugs. So this is
more of asking whether there are other CYPs that
seem important, because we know there are quite a
few drugs that are a substrate of 2CA. So whether
it's important to evaluate the inhibition
potential, of the other drugs, when you answer, you
could include others or maybe a specific set, only
certain CYPs that are important to evaluate right
now.
DR. VENITZ: Any comments?
DR. WATKINS: One of the issues in the Bay
375
Call litigation is whether 2CA inhibitions should
have been routinely part of drug development back
in the, I guess, the midnineties, and it would
certainly seem, for those who don't know,
gemfibrizol inhibiting 2CA appears to be a relevant
mechanism for the rabdomyalisis there. And it
would seem to me if you knew and demonstrated that
your drug was largely metabolized by 2CA, it would
now be incomprehensible why you wouldn't do
interactions at least with gemfibrizol.
So certainly, for 2CA, it would seem to me
that should be part of the guidance.
DR. HUANG: We actually have a case where
we did recommend a study with gemfibrizol with a
2CA substrate. And now, the question is if a new
molecular comes in, do we need to ask routine
evaluation of in vivo interaction with CYP2CA
substrate?
DR. WATKINS: So for clarification, are
you saying when there's no evidence from in vitro
studies that it's metabolized by 2CA?
DR. HUANG: Yes, right now, we're talking
376
about the effect of new molecular entity on others.
If this new molecular entity is a CYP2CA substrate,
because they're not the substrate of the other five
major CYPs, and 2CA is a major substrate, then, we
would recommend a study with the two CYP2CA
inhibitors that based on literature data.
But my question right now is if a new
molecular entity, when we evaluate its ability to
affect other drugs, do we routinely ask to evaluate
CYP2CA?
DR. WATKINS: I think I understood it
correctly, and my answer would be yes, that that's
a relevant pathway for certain statins and already
has a track record of problems. It's Taxol's major
pathway; rosyglydazone; it would make sense to me
to incorporate that into the document.
DR. HUANG: So we would add to the five
major CYPs perhaps CYP2C8?
DR. WATKINS: I would say so, yes.
DR. VENITZ: What would be your UGT1A1
inhibitor that you would recommend be studied?
DR. HUANG: Right, actually, I would not,
377
but this is thrown out as a question partly because
we haven't seen significant interaction. I think
earlier on, there was a question about UGT1A1
inhibition or actually this morning about
irinotecan. I don't think we have seen an
inhibitor which can deplete the activity as much as
a poor metabolizer status that would cause the
depletion of the UGT activity, so we have not
putting that as a recommendation of evaluating a
drug's ability to inhibit UGT1A1.
DR. VENITZ: You want to take it off the
question, then?
DR. HUANG: We could, unless there are
others.
DR. MCLEOD: Is it known how many
companies are not currently screening for these
three? Because many companies are already looking
at these three because of the known polymorphisms
and trying to predict risk.
DR. HUANG: For a new molecular entity as
a substrate of these, yes. This has been done.
But as routinely to evaluate its ability to inhibit
378
these, no, not consistently. And the latter one is
my question.
DR. MCLEOD: Right, thank you.
DR. SADEE: I think that clearly, we
should be somehow going on record to say that the
potential for interaction should be assessed.
Whether we would want to recommend for all these
three genes and their products to recommend
clinical drug interaction studies, that's a
different question. But I think we need to go
forward and say these are important potential
factors in drug-drug interaction.
So in particular, if we don't have any
inhibitors, it would appear to be difficult to
recommend at this point clinical studies.
DR. VENITZ: Larry?
DR. LESKO: Yes, I just wanted to make
sure I understood Paul's comments, because I don't
think this fits the Bay Call situation, because the
question, as Shiew-Mei's asking it, is if I have a
drug that is a substrate for these enzymes, not a
substrate affected by another drug for these
379
enzymes. So, in other words, if the enemy was a
substrate for these enzymes, would you want to do
clinical studies based on the in vitro? Isn't that
what you just said?
DR. HUANG: No.
DR. LESKO: Okay; could you just rephrase
that so I understand the question?
DR. HUANG: Well, in our guidance, we
actually said as a substrate, it's important to
study other than the five major CYPs, because if
there are not substrates for those five major CYPs,
you need to evaluate, for example, 2B6, 2C8 and
others and UGT 1A1. You need to know if it's a UGT
substrate, so later on, we can see the variation in
genetics, how that affects the pharmacokinetics.
But right now, I'm asking whether it's
prudent to recommend routine evaluation of a new
molecular entity's ability to inhibit--that's not
the same as the substrate--to inhibit these
enzymes.
DR. LESKO: Yes. That's my point. Bay
Call didn't inhibit gemfibrozil. It was the other
380
way around.
DR. HUANG: No, no, no, but Bay Call,
cerebrostatin is being found to be a substrate of
CYP2C8 and other transporters and UGT. So
gemfibrozil would affect the part of the
interaction of gemfibrozil and cerefostatin could
be through CYP2C8.
DR. LESKO: Well, creating the scenario,
the scenario is the cerebrostatin is the new
molecular entity, and the question is does that
affect the metabolism of other previously-approved
substrates for these enzymes?
DR. HUANG: Right; it would not.
DR. LESKO: Yes.
DR. HUANG: But to come back to Paul's
question, now, with a new molecular entity such as
cerebrostatin, if we have, if we know that it's a
CYP2CA substrate, based on the new concept paper,
we would have recommended a gemfibrozil type of
study. We did have that statement in our guidance,
our concept paper. We have said that if it's a
substrate.
381
DR. LESKO: Right.
DR. HUANG: But as an inhibitor, okay, if
cerevosin is right here, other drug that's being
approved which may affect its, okay, say it's 2CA
or many of these glydazones, they're CYP2CA
substrates. So if another NME that we're
reviewing, should we ask that it be evaluated as an
inhibitor of CYP2CA, because they may interact with
many of the glydazones?
DR. LESKO: Yes; it's just two different
questions.
DR. HUANG: But I'm asking this question,
not the other question.
DR. LESKO: The new molecular entity could
be the so-called offending drug, or it could be
the--
DR. HUANG: Yes, offending drug.
DR. LESKO: Yes.
DR. HUANG: We're only talking about
offending drug here.
DR. LESKO: All right; it's the offender.
DR. HUANG: Yes.
382
DR. WATKINS: And just, Larry, because
it's getting late, and I'm getting confused, too,
about the two different things, but it would be
like if somebody developed a new gemfibrozil which
was an inhibitor of 2C8, and that appears to have
contributed to the recall of Bay Call because of a
drug interaction, and so, we already have a
precedent that caused a serious problem, it only
makes sense to me to included 2C8 inhibition in
the, you know, the next test tube and the line of,
you know, recombinant enzymes.
DR. GIACOMINI: It says clinical study.
It's not whether to put it in the test tube.
DR. WATKINS: All right; so you meant in
terms of coming up with specific probes for 2C8,
for instance?
DR. HUANG: Yes, and I'm actually asking a
general question: should we evaluate the other
pathway besides the five major CYPs?
DR. WATKINS: Okay; because that's the way
she rephrased the question is that we know 3A4, you
know, 1A2, et cetera. Should we be adding 2B6 and
383
2C8 all the way back to everything? And my answer
is yes, that should be done, and I think an in vivo
study should be done if there's evidence of
inhibiting 2C8 in vivo. So I'm just going to carry
it, like, 3A4 through the whole process. That's
what I meant, anyway.
See, I realize this says just clinically
but--
DR. HUANG: But it's clear based on what
you said.
DR. WATKINS: Whereas 1A1 and 2B6, I
think, is much less clear, but 2C8, there's a track
record.
DR. HUANG: Thank you.
DR. HALL: I think given, of course, that
it passes the test of your definition of not or
is--
[Laughter.]
DR. HALL: So if the I over KI ratio is a
certain number, then, whether we have other
inhibitors of 1A1 or not, the new entity would be a
good inhibitor of 1A1 predicted from that in vitro
384
study, correct?
DR. HUANG: 1A1? You're talking about
UGT1A1?
DR. HALL: The UGT1A1, for example.
DR. HUANG: Yes.
DR. HALL: So, you know, in 2B6, even
though there's not many 2B6 substrates that are
sufficient, if you were to coadminister it with
one, you would be concerned if the I over KI ratio,
however we define it, is sufficient.
DR. HUANG: Right.
DR. HALL: So I don't see why these would
be special. You would simply treat them just like
3A.
DR. HUANG: Right. One of the reasons we
put it this here, in order for us to put in a
guidance, we need to have probe substrates,
inhibitor, inducers to recommend. So if we have a
good probe to recommend, then, we would put it in
the guidance. If we don't have a good probe--we're
talking about metabolizing enzymes, not the
transporters--then, we usually do not. But we did
385
put in 2CA, 2B6 substrates and inducers. I don't
think we have an inhibitor for 2B6 yet based on our
discussion in November. But I know what you're--I
understand your comments.
DR. SADEE: But I think there needs to be
another qualifier here. Those are minor
cytochromes in terms of quantity, and if a compound
is a substrate for 2C8, let's say, and it's also a
good substrate for 3A4, then, it doesn't make any
sense to study this in further detail. So it needs
to be said that the evidence suggests that there
are substrates and that this is the major pathway
of metabolism.
DR. HUANG: Correct, correct.
DR. VENITZ: Okay; are we ready for a
vote?
Okay; then, I think I'm going to start
with Dr. Barrett.
DR. BARRETT: Yes.
DR. VENITZ: Dr. Blaschke.
DR. BLASCHKE: As amended, yes.
DR. VENITZ: Dr. Capparelli?
386
DR. CAPPARELLI: Yes.
DR. VENITZ: Dr. D'Argenio?
DR. D'ARGENIO: Abstain.
DR. VENITZ: Dr. Davidian?
DR. DAVIDIAN: Abstain.
DR. VENITZ: Dr. Derendorf?
DR. DERENDORF: Yes.
DR. VENITZ: Dr. Giacomini?
DR. GIACOMINI: Yes.
DR. VENITZ: Dr. Hall?
DR. HALL: Yes.
DR. VENITZ: Dr. Jusko?
DR. JUSKO: Yes.
DR. VENITZ: Dr. McLeod?
DR. MCLEOD: Yes.
DR. VENITZ: Dr. Sadee?
DR. SADEE: Yes.
DR. VENITZ: Dr. Watkins?
DR. WATKINS: Yes.
DR. VENITZ: And I put my yes in, so we
have 11 yes, no noes and two abstains.
DR. HUANG: Jurgen, can I clarify, because
387
I have heard some say yes with the amendment. So I
assume the amendment was based on Dr. Watkins'
comment that we consider 2C8? And the others are
just as-is, correct?
DR. VENITZ: Yes.
DR. HUANG: Okay.
DR. SADEE: What about the other--it has
to be the major metabolic pathway.
DR. HUANG: Right; that's on the substrate
side. Here, we're talking about inhibitor.
DR. VENITZ: Okay.
DR. HUANG: The next question is related
to the transporters. We said does the current
evidence support recommendations that drug
interactions based on other transporters, such as
OATP or MRP, be recommended for clinical study
during drug development? And I believe because the
answers from questions 2, 3, and 4 are relatively
positive, so I guess we could move on to this one.
If those were negative, then, we wouldn't ask this
question, because PGP is much more developed a
field.
388
So I would go ahead and ask number six.
DR. GIACOMINI: I think it's hard to do
this at the end of the day, to present all of the
evidence to suggest that something might be
clinically relevant for us to begin to put this in
the guidance. So I have some thoughts about it,
but it's--there are some other transporters:
OATP1B1 in particular is one that we should be
thinking about.
And what is the evidence there? Well,
there's good evidence, first of all, in cell
culture that OATP1B1 and the statins, interacts
with the statins. There is a genetic polymorphism
in OATP1B1 that has now been shown in three or four
clinical studies that when that transporter is
polymorphic, pravostatin levels then go up. So
there's polymorphism evidence; there is in vitro
cell culture evidence; there is drug-drug
interaction.
Now, these are, again, not clean. So you
take a drug like pravastatin. It interacts with
OATP1B1. It's not a CYP substrate. And when you
389
give it with cyclosporin, which is dirty, you get a
profound eightfold increase in the area under the
curve. Similarly, pitavostatin, which is another
one which is primarily--it's not a CYP substrate.
It's primarily a transporter thing. When you give
pitavostatin, when you give cyclosporin with
pitavostatin, you see, like, a four and a half fold
increase in area under the curve. So they're
increasing clinical drug-drug interactions showing
or suggesting highly that OATP1B1 is involved, and
then, there's genetic data.
So it's one that I think we should
certainly be considering as part of this guidance.
That's one that you're asking me to present at
5:00. And then, the other area, which I don't know
how the Committee feels about this, is just renal
transport interaction. So I had read the 1997
guidance, and there's nothing in there about--at
least I didn't see anything in there about renal
transport interactions, and there are known
probenecid versus penicillin, even therapeutic
interactions that people use those two drugs
390
together, actually, to enhance the effects of
penicillin.
So if I have some thoughts about, you
know, if a compound is secreted or if your in vitro
studies are suggesting that they're interacting
with some of these OATs, kidney-specific OATs,
particularly OAT1 and OAT3 or kidney-selective
OCTs, OCT2, which is only in the kidney, then, you
may want to consider doing a probenecid interaction
study for the N ions, and then, for a CAT ion, you
might want to consider doing, for example, a
somatadine interaction, if that's--so those are
renal transport points, and I think it would be
appropriate to mention, at least in this guidance.
It's drug-drug interactions that should only
concern the liver.
DR. HUANG: And just to clarify, so if
we--I mean, we do have certain studies that we look
at the competition of ectosecretion on renal
levels, although the labeling only states the
drugs. We do not extrapolate to other
transporters, and we do not currently name the
391
transporters. Do you think we're at the stage to
name the transporters when we report this type of
interaction?
DR. GIACOMINI: Well, okay, so, for OAT3,
there's a knockout mouse that when the OAT3 is
knocked out, the cephalosporin renal elimination
goes way down. So you've got knockout mouse
studies, and then, you have studies showing, you
know, certain affinities for OAT3. So those are
the two levels that you have for OAT3.
For OAT1, there's not a knockout mouse.
You just have cell culture evidence. And you know
that these anines are interacting.
DR. MCLEOD: Kathy, do you think it needs
to be so specific, though, in the language?
Because you've identified several different
families where it's important. There will be more
coming. You didn't mention the transporters, which
from your own work and others, are also going to be
important. I almost think, like, that the language
needs to be more general, saying transporters, any
transporter that's shown to be--any drug that's
392
shown to be a substrate for a transporter needs to
be followed up if it's a main route of transport;
if there's some data.
Because if we get into the point where it
has to be a--only a named transporter on the list,
even if you have it on the Web, and it's dynamic,
you know, it's too new--the field is moving too
fast for this guidance to be changing every couple
of minutes.
DR. GIACOMINI: Yes; I guess what I did
when Shiew-Mei asked me to consult was I just
looked for the most compelling examples, not the
ones that, you know, the field is moving fast, and
I think we would be changing every week. But the
statin interactions are pretty strong; in
particular, the statin interactions with OATP1B1
look pretty compelling right now. And then, of
course, the renal transport interactions, which
have been historically around for so many years are
more or less compelling.
But again, I feel like the--I, personally,
feel like it would be nice if people saw the papers
393
and got the irinotecan book, you know, something
like that on some of these so that they could see
the evidence themselves.
DR. MCLEOD: And I've had the benefit of
seeing you present this data and others.
DR. GIACOMINI: Right.
DR. MCLEOD: And there is very good data
for a lot of these.
DR. GIACOMINI: Right.
DR. MCLEOD: So I think you're right that
these are at least on people's radar screens.
DR. GIACOMINI: Right.
DR. MCLEOD: I think the companies, most
of the big companies, you know, it is on their
screen.
DR. GIACOMINI: Yes, it is, but I don't
know whether it's ready for this guidance.
DR. HUANG: Just for information, we do
have--we have seen in vitro data or animal data on
various transporters. So the question from our
reviewers is are we ready to recommend a followup
when it's shown to be a substrate or an inhibitor?
394
And that's why I put in this question. And these
are real-time review questions.
DR. VENITZ: And I guess my sense is I
think we are ahead of the science. I mean, here,
you're setting rules for large regulated industry,
and I don't think we're there yet. So maybe if you
come back in a year or two years from now, we'll
have more information. That's my personal opinion.
We'll have more information. But right now, I
can't agree with that.
DR. GIACOMINI: And I think he can't agree
with it, because we didn't have the time to
present, although you didn't see the papers and all
of that, so you have to look at that and see where
the evidence is. But we just didn't have time to,
because there is, on one of them, at least, there's
more and more compelling evidence, but I agree.
DR. LESKO: Yes, one of the questions I
have is how do you translate information in a sort
of cutting edge area into a label? I mean, with
the CYP enzymes that we're quite familiar with,
there's studies done in vitro; there's studies done
395
in vivo, and then, we label compounds with
information about drugs that were not studied,
necessarily, but are part of a class of 3A
substrates that are sensitive or modestly sensitive
or something like that. So the value of the
information becomes larger in magnitude, because
you can extrapolate.
My question then becomes, in this area of
transporters, when you say this cephalosporin or
that cephalosporin, is it then only that
interaction that's of relevance? I.e., can you go
beyond that to say, well, it isn't just the two
drugs I studied in the clinical study, but it also
would apply to this drug and that drug and other
drugs. Do we know enough about the information to
get more out of the study than simply two drugs
interact; that is leveraging the information for
the package insert?
DR. BARRETT: I come back to Howard's
point here, though. I don't know that we need this
level of granularity. I mean, I think if you
rephrase this in a more open fashion, and you don't
396
need to tell your child don't put your hand on the
stove if you told him not to put it in the
fireplace. So I don't know that you need to do
that.
DR. DERENDORF: Well, I also think that it
really depends. I think the general answer to that
is very, very difficult, and coming back to what
was said earlier about the exposure response
relationship, if there is a likelihood that this
may be relevant, that depending on the PKPD
properties of the compound, it's a different story
than when I have a very safe compound, am I really,
you know, if it happens or not, it's nice to know,
but it really wouldn't make that much of a
difference.
So I think that needs to enter the
decision tree, too, at some point.
DR. VENITZ: Any other comments?
Okay; ready for the vote, Dr. Watkins?
DR. WATKINS: I know it's a tough one. I
mean, it's so clear that transporters and uptake
transporters are going to be so important in the
397
disposition of drugs. And to come back to Bay
Call, there was some evidence of OATP inhibition
and things. But unfortunately, the science is so
new, there aren't good probes or understanding of
regulation-specific inducers. So I think anything
more than just encouraging, you know, more research
in the area is very hard at this stage. So I don't
know whether that's a yes or a no.
I guess it's a no, because, well, I guess
we don't even have--oh, there it is, yes, because
you're saying clinical study, and I don't think we
really have the tools to clinically study it other
than maybe pravacol for 1OATP, so I guess I'm no.
DR. VENITZ: Okay.
Dr. Sadee?
DR. SADEE: I agree with the principle
that wherever you find a single gene product to be
important in drug-drug interactions, it is
essential to study it further. And the evidence is
beginning to appear, but I cannot see that we can
prescribe clinical studies at this point. So I
would like to abstain, but I like a more general
398
approach here.
DR. VENITZ: Dr. McLeod?
DR. MCLEOD: Yes.
DR. VENITZ: Dr. Jusko?
DR. JUSKO: On one hand, it seems highly
advisable that if a drug is following a certain
pathway, it's the major pathway, that any
interactions with it should be studied. But we
haven't been given enough evidence for this whole
arena for me to say yes as yet, so I'm going to say
no.
DR. VENITZ: Dr. Hall?
DR. HALL: I think I would go with a no as
well given the context that others have already
mentioned.
DR. VENITZ: Dr. Giacomini?
DR. GIACOMINI: I'm going to go with a yes
that there are specified transporters that we could
be looking--requiring clinical studies on and
drugs, specific drugs.
DR. VENITZ: Dr. Derendorf?
DR. DERENDORF: I go with a no unless
399
there is evidence that there is a high likelihood,
so not as a general recommendation.
DR. VENITZ: Dr. Davidian?
DR. DAVIDIAN: Abstain.
DR. VENITZ: Dr. D'Argenio?
DR. D'ARGENIO: Abstain.
DR. VENITZ: Dr. Capparelli?
DR. CAPPARELLI: For the specific
transporters listed there, I would have to say no,
but I think that the issue of putting a general
statement in would be highly recommended.
DR. VENITZ: Dr. Blaschke?
DR. BLASCHKE: I would agree with that. I
think there should be something in there about
transporters, something that can be updated.
DR. VENITZ: And Dr. Barrett?
DR. BARRETT: Yes.
DR. VENITZ: And I would put my no in with
the recommendation to maybe come back at a future
meeting and talk about specific transporters and
probe substrates, probe inhibitors.
DR. HUANG: One clarifying question, when
400
Dr. Watkins says maybe with the exception of
prevastat and OATP1B1, is that--did you say that
or--
DR. WATKINS: Maybe. Was it intelligent?
I can't remember.
[Laughter.]
DR. HUANG: That's all right.
DR. WATKINS: I mean, that's why I'm sort
of torn with this. I mean, there is the pravacol
example, so there's a probe, but I don't know the
studies that have validated it. I think as Kathy
said, we really haven't heard much about
transporters here, so, you know, I'm all for
clinical study of these things, and that's all I
can say right now.
DR. HUANG: Okay, thanks.
DR. VENITZ: Okay; the final vote is three
yes, seven no, and three abstain.
DR. HUANG: The next questions are related
to induction.
Okay; so there are two questions: one of
them is on--maybe I'll go to question A first,
401
because that's how it was presented: if a new
molecular entity induction effect on CYP3A in vitro
is negative, and it's acceptable not to recommend
in vivo studies, not only just CYP3A but also 2C9,
2C19 and 2B6; if you do not agree with 2B6, we
could take it out, because right now, we're only
recommending the major CYPs: 1A2, 3A2, 2C9, 2C19.
DR. VENITZ: Paul?
DR. WATKINS: If I could just ask for
clarification from John, actually: you were saying
that phenytoin was negative, at least in one human
hepatocyte induction study, and you thought that
was because the hepatocytes might have been
maximally induced, in which case the positive
control would have been negative?
I mean, my question is, and maybe I should
put in a context, because I've talked to Shiew-Mei.
What we're really voting on here is the concept
that every single drug ever developed from here on
either is given to people and probes either singly
or in a cocktail are done to see if they induce it.
And if you don't want to do that, you can do
402
cultured human hepatocytes and see whether the
induction is 40 percent of a positive control, and
if it's not, then, you don't have to do those
studies.
And since the clinical studies are further
in development and requires a lot of drug and
everything, what it's basically saying is every
single drug ever developed from now on, you can
correct me if I'm overstating the case, has to go
through a human hepatocyte study at some point in
its development. Practically, I think that would
be the outcome.
And the concern that I have is just that
I'm unaware of the data that would really
standardize this thing as being a routine part in
drug development, and we heard about all of the
different cells, and if the liver is ischemic, the
pericentral hepatocytes are gone, and you just have
the periportal hepatocytes, and maybe people can
cryopreserve a whole bunch of hepatocytes from 50
different donors, so genetic polymorphisms is
important, and you can refreeze the same aliquot,
403
and it will all be standardized, and it will all
make sense.
But from my perspective, I have just not
seen any data to suggest it's that robust. Now,
that would be acceptable in my opinion because I
think it is the best single test for induction if
it weren't such a precious resource to us
academicians. I mean, I don't know how industry is
getting all these to do all these studies. I just
know that we academic people have a very hard time
getting them.
So I think there's a cost of, you know, of
doing this, and so, that's the basis of what I'm
saying. You mentioned that there is a clear
clinical significant drug interaction with
phenotone. It's on a short list of drugs where
induction is really important, and didn't you say
that it was negative in a human hepatocyte culture
study?
DR. STRONG: Yes, this was in some data
that Ed had in his slide. You know, I think in
most studies, you'll find that it would meet that
404
40 percent criteria. I think what I was pointing
out was design of experiment is very careful, you
have to be very careful with; i.e., these
particular hepatocytes appeared to, you know, be
induced with their background or basal activity for
three or four was very high, compared to, say, even
looking at the figure A, which was the 2B6.
So what I was talking about was I still
don't know what number quantitatively would be good
myself, and I think that's what we're trying to
discuss here. I think a lot of it may be just due
to the particular hepatocytes you're using and the
design of the study.
You were mentioning, you know, the
availability. You know, that's a question I don't
know either myself. Certainly, folks here in PhRMA
would know. I agree with you that they're
expensive, but--
DR. WATKINS: Well the price is going to
go way up.
DR. HUANG: Right.
DR. WATKINS: --if we endorse this,
405
obviously.
DR. HUANG: I'd like to clarify. The in
vitro methodology is only one additional method
that we think that could be used to evaluate
induction, but it's not required to have hepatocyte
studies done. It obviously can be achieved through
in vivo study. It could be a specific study; it
could be a cocktail study; it could be a population
study. We're just adding an additional tool that
we think is acceptable to study.
So it's important to the issue that you
raised, but this is only one additional tool. So
with that, I would like to amend my question:
based on the mechanism of induction that we have
heard through various nuclear receptors, I would
like to say if the induction in 3A is negative,
which could be in vitro or in vivo, that we do not
need to assess 2C9 or 2C19, because they would have
been coinduced. So if a negative 3A could prevent
us from conducting an additional study about 2C9 or
2C19, that's my question.
So it could be a different, because of the
406
mechanism of induction, so I'm amending my
question, number eight. Number seven is specific
about in vitro methods, so we can come back later,
but I'd like to amend my question, so that we don't
have to be considering the appropriateness of the
hepatocyte preparation.
DR. HALL: I think again, we have to
discuss the not or the negative part, how that's
defined. And I think, you know we could define it
rigorously like Dr. LeCluyse did, which
incorporated many aspects, including RNA
quantitation, which is quite rigorous and would be
comforting, I think. But that's an enormous
burden, then, I think, on the industry to not only
procure all the hepatocytes but to do all the other
parts to that that would make it a water-tight
conclusion that it's negative.
So I think again, it's one of those
questions where you really have to state what being
negative means. What would you accept as being
negative?
DR. HUANG: So what about if we have
407
conducted an in vivo study with medazolam, and it
shows no change in medazolam AUCs with this new
molecular entity? Could we say that you do not
need to investigate whether this drug also induced
2C9 or 2C19? And perhaps you're hinging on the in
vitro data to make that conclusion. I'm doing an
additional leap of--not leap of faith; if you look
at mechanism of induction. If they're coinduced.
DR. JUSKO: When you do inhibition
studies, you very nicely take into account an I
over KI ratio. These in vitro induction studies
lend themselves to calculating EC50 values for the
induction, and in addition, you can bring in a CMAX
for the exposures, expected exposures in animals or
humans. It seems like these kinds of quantitative
indices are needed to augment this kind of
recommendation.
DR. MCLEOD: We were presented with data
showing that hitting the nuclear receptor caused
induction of 3A4 and 2C9 and a bunch of others. I
didn't remember seeing any data saying that that's
the only mechanism for inducing 2C9, 2C19, and
408
whatever else you want to write up there.
So do you have any data to share with us
to help on the voting how--if there are any other
realistic mechanisms of induction? Because it
seems like there's got to be something else.
DR. HUANG: Maybe Dr. LeCluyse can address
based on in vitro. But I think the information was
that if you induce 3A through PXR, if the 2C9 and
2C19 through PXR, then, you would have seen it.
But as for other mechanisms, so far, we don't have
a drug which is a pure CAR--
DR. MCLEOD: I'm thinking of false
negatives, basically.
DR. HUANG: Right, we don't have a drug.
So far, we don't have a drug that's based on in
vitro data to show that's the case. Until we have
a drug which is a pure CAR receptor effective,
then, for now, then, I don't think we'll see a
false negative.
DR. LECLUYSE: So basically your concern
is is there something that might be missing
mechanistically, and is it as simple as we portray
409
it as these three nuclear receptors, which is
really what I'm proposing. And we have come, you
know, round and round with this ourselves over the
years. We've asked ourselves the same questions:
is it as simple as if you don't see a compound
activating CAR or PXR, is it sufficient to exclude
any other possible mechanism?
And what's interesting is that seeing all
the evidence to date, not only our own but out
there in the literature, including if you look at
all the observed, clinically significant drug
interactions that are due to induction, and to me,
that's the question, I think, that's at hand, you
can explain every one of those through these three
nuclear receptors. And I think, you know, I think
Wolfgang brought up a point about some of these
other cofactors and some of these other
transcription factors that are involved in just
normal gene regulation, and, you know, whether it's
basal expression or induced expression, they play a
role.
But the question was the clinically
410
relevant drug interactions that have been observed
in those events could all be explained by these
three nuclear receptors or these three receptors.
And it seems at least for the human P450 enzymes
that they're regulated by these three receptors and
can be explained through these.
So, you know, we're convinced to, like,
here I say our evidence as well as others that
you're pretty much covering all your bases or most
of your bases through these mechanisms; that at
this point in time, that's where the science is at.
DR. MCLEOD: Thanks. You're on the
record.
DR. BARRETT: Shiew-Mei, instead of maybe
considering whether or not this test is adequately
sensitive to protect against induction of the other
CYPs, I just wonder if this guidance needs the
burden of having that statement in it, because I
think if you don't have it, it's going to be up to
the sponsor to investigate induction where they
think it's appropriate.
If they see CYP3A4 not involved as an
411
inducer, they're not going to do those studies.
However, you may see, either with population
analyses or otherwise, some evidence for induction,
and in that case, they're going to have to
investigate it.
I mean, I understand the spirit of trying
to reduce the redundant studies or eliminate
unnecessary or noninformative ones, but this seems
to be an additional burden to the guidance that
maybe it doesn't need.
DR. WATKINS: Sorry, and then, I will shut
up, but there are things called gratuitous
inducers; there's things that induce pathways that
aren't involved in their own metabolism; so just
that it's not a 3A substrate doesn't mean that it
couldn't induce, you know, bind and activate PXR.
Let me give a hypothetical example:
there's a drug that there's been no induction study
in two animal models and an in vitro, you know,
PXR, you know, binding and transcriptional assay;
there's no effect at all. The question is
what--show me the data that the human hepatocyte,
412
cultured human hepatocytes is going to add
significantly to the decision making of whether an
in vivo study should be done there. I mean, what
is the human hepatocyte--I mean, just where is this
data that this is going to be worth this precious
resource on an industrial scale?
Relatively early in development, which is
where I would do it if this guidance came out, and
right at lead candidate selection is when I'd try
to do a cultured hepatocyte study just to know what
was, you know, coming down the line. And it just
strikes me that I've not seen this data. I mean,
for instance, all the drugs that are known to be
clinically relevant inducers, say, through PXR, and
the whole list of drugs that aren't at all, like
niphetapine, for instance, is a PXR ligand,
activates PXR, but there's no drug interaction that
I'm aware of that's due to niphetpaine inducing
metabolism through PXR. And Ed, you may know about
it.
But where is the data that really
critically evaluates the added value of early human
413
hepatocyte studies for induction? We know the
receptors; we should be able to see whether they
bind them and activate them, and that should be the
initial step, and if it's negative, I want the data
that going to human hepatocytes is adding the
enormous costs and resource that that represents.
DR. VENITZ: Okay; Shiew-Mei, why don't
you rephrase the question so we can vote on it?
Because you were going to make an amendment, if I
remember correctly.
DR. HUANG: Yes, although no committee
members have commented on in vivo. If in vivo 3A
shows negative induction, and we should--
DR. VENITZ: Should say in vitro or in
vivo.
DR. HUANG: Yes.
DR. VENITZ: Okay; so what we're voting on
is question eight with the addition of in vitro or
in vivo.
DR. HUANG: And I would just comment on
2C9 and 2C19. If a new molecular entity induction
effect on CYP3A in vitro or in vivo is negative, it
414
is acceptable to not recommend any studies with
substrates of 2C9 and 2C19.
DR. VENITZ: Okay; I think we are starting
with Dr. Barrett this time.
DR. BARRETT: No.
DR. VENITZ: Dr. Blaschke?
DR. BLASCHKE: As rephrased, I think it's
acceptable. I'd say yes.
DR. VENITZ: Dr. Capparelli?
DR. CAPPARELLI: In the definition, in the
rephrasing of it, if there is no in vivo or in
vitro indication of inhibition, then, I would say
yes. So there's the situation where you may mask
induction by having inhibition as well.
DR. HUANG: We're talking about induction
here.
DR. CAPPARELLI: No, I understand.
DR. HUANG: Oh, okay.
DR. CAPPARELLI: But, like, with
ritonavir, if you gave a drug that induced but also
inhibited, you may miss it in a 3A screen, and it
may still have an impact on induction if it's not
415
inhibiting the 2C system.
DR. VENITZ: Dr. D'Argenio?
DR. D'ARGENIO: Abstain.
DR. VENITZ: Dr. Davidian?
DR. DAVIDIAN: Abstain.
DR. VENITZ: Dr. Derendorf?
DR. DERENDORF: Abstain.
DR. VENITZ: Dr. Giacomini?
DR. GIACOMINI: Yes.
DR. VENITZ: Dr. Hall?
DR. HALL: I think as rephrased, then, I
agree with what Paul is saying, but this doesn't
say anything about hepatocytes. It could equally
well be a reporter system. So in that context, I
think I would say yes.
DR. VENITZ: Dr. Jusko?
DR. JUSKO: Yes.
DR. VENITZ: Dr. McLeod?
DR. MCLEOD: Yes.
DR. VENITZ: Dr. Sadee?
DR. SADEE: Yes.
DR. VENITZ: Dr. Watkins?
416
DR. WATKINS: I'm just getting irritable,
but I feel like saying no at this point. But I
think the qualification--
[Laughter.]
DR. WATKINS: --is if you know that it
acts through PXR, if you know that, at least from
the evidence I know, then, demonstrating it does
one of these things in vivo, you know, gives you
your answer. You don't have to test for all of
them.
So if that means my answer is yes, then,
it's yes.
[Laughter.]
DR. VENITZ: You tell me.
DR. WATKINS: I still think that the human
hepatocytes is hooked in here somewhere into this,
but, I mean, they only go together if they're all
being activated by PXR. And it sounds like all the
data makes that acceptable. So the real issue is
does your drug activate PXR? And then, you can see
whether it induces one of these and assume the rest
go along. But there has to be that PXR link, I
417
think.
DR. VENITZ: I think that would be a yes.
DR. WATKINS: Yes, that's a yes.
DR. VENITZ: Okay; I'll throw my yes in,
and we have three abstains, one no, and eight
yeses, okay?
Then, question number seven, Shiew-Mei?
DR. HUANG: Question number seven is early
on clarified by Dr. LeCluyse. When we say that the
in vitro induction, and here, we look at increase
in enzyme activity, is more than 40 percent of the
positive control, and the 40 percent could be any
of the three with a preparation, so the mean value
could be lower than 40 percent, but it's any one of
them, because you need to have them all lower than
40 percent before you would declare it's negative.
So with that clarification, the question
is is 40 percent the proper positive control?
DR. VENITZ: Okay; any questions or
comments?
DR. SADEE: But if you have an inhibitor,
ritonavir again, you get a decrease, so--
418
DR. HUANG: Yes, in our guidance, we
actually have some provision. You need to look at
the inhibition. If there's a mechanism-based
inhibition, then, you look at mRNA and other
parameters in addition to enzyme activity. So that
would have taken care of this.
DR. GIACOMINI: Is this the human
hepatocyte again for--
DR. HUANG: Yes.
DR. GIACOMINI: It absolutely is. So it
sets it as a standard, then.
DR. HUANG: This is, yes.
DR. GIACOMINI: Like not a reporter or
anything like that assay.
DR. HUANG: Here it's human hepatocyte.
DR. GIACOMINI: Okay.
DR. VENITZ: Hartmut?
DR. DERENDORF: It needs to be related to
a concentration, as Dr. Jusko pointed out, some
EC52P concentration term in there.
DR. HUANG: Yes, here in the appendix of
the concept paper, we recommended if we know the
419
concentration that we expected using tenfold or up
to 100-fold of concentration. So you have a
spectrum of concentration because of sometime, you
see an expected U-shaped or inverted-U effect, so
we need to look at various concentrations. So we
did have some detail in the concept paper about
what concentration to use.
And right now, this question, we're
looking at the maximum, maximum induction, and we
did not take into account EC52, even as it was
discussed. But this particular criterion was based
on that.
DR. SADEE: But in the human hepatocytes,
you then have to screen for those that have low
basal activity in order to get a high percentage.
Is that correct or--
DR. HUANG: Yes, our only recommendation
is that you need to have positive control, and
positive control needs to work. And we did put in
a reference value in the guidance on what should we
expect when certain concentrations of rifampin are
incubated with this particular system. What should
420
we expect to see? And only when those values are
valid, then, we will consider this next step.
DR. VENITZ: Any other comments?
Okay; then, I think, Dr. Watkins, you're
the one to go first.
DR. WATKINS: Now, I'll say no.
You know, the implication here is that
human hepatocytes have been widely standardized,
and companies can sprout all up and come up with a
reliable 40 percent estimate and a cost-effective
way that will be like an Ames test and yes-no
determining the subsequent development, and I have
just not seen any data that supports that, so no.
DR. VENITZ: Dr. Sadee?
DR. SADEE: Yes.
DR. VENITZ: Dr. McLeod?
DR. MCLEOD: No.
DR. VENITZ: Dr. Jusko?
DR. JUSKO: No.
DR. VENITZ: Dr. Hall?
DR. HALL: I would like to say yes. I'm
not sure about the 40 percent, and the details are
421
important, but in principle, yes.
DR. VENITZ: Okay; Dr. Giacomini?
DR. GIACOMINI: No.
DR. VENITZ: Dr. Derendorf?
DR. DERENDORF: No.
DR. VENITZ: Dr. Davidian?
DR. DAVIDIAN: Abstain.
DR. VENITZ: Dr. D'Argenio?
DR. D'ARGENIO: Abstain.
DR. VENITZ: Dr. Capparelli?
DR. CAPPARELLI: No.
DR. VENITZ: Dr. Blaschke?
DR. BLASCHKE: No.
DR. VENITZ: Dr. Barrett?
DR. BARRETT: Yes.
DR. VENITZ: And I throw my no in.
Seven noes, three yes, and two
abstentions.
DR. HUANG: The last two questions: as
related to the multiple inhibitor studies, and it's
a long question. We say is it acceptable to
recommend that under certain conditions, and in
422
particular, when we're evaluating QT prolongation
effect, it's important to determine the maximum
exposure of new molecular entities. Actually,
these are in the ICH guidance on QT. It was the
detail that we're asking for recommendation.
The maximum exposure, it's probably not
what we should be discussing for this guidance. I
mean, the comment should be for the other guidance.
But with that guidance recommendation, how would we
achieve the maximum exposure? We can do that with
a single inhibitor or multiple inhibitor, so this
would be the focus of discussion when there is more
than one pathway or under multiple impaired
conditions, such as renal impairment plus
co-administration of an inhibitor.
DR. VENITZ: A couple of comments: I'm
still not sure that you can't predict this based on
the individual interactions that you know, and
then, use modeling and simulations to predict what
the maximum exposure would be.
Number two, you obviously would want to do
this for drugs where the stakes are high, meaning
423
you're really worried about toxic effects. Well,
those are probably the ones that you ethically
couldn't do a study like this unless you reduce the
dose. Well, if you reduce the dose, then, you have
to have some idea about what to expect; in other
words, you have to do modeling and simulations to
figure out how to adjust your dose.
And the last thing is to do those kinds of
studies logistically to me is a nightmare, and I'm
not sure what you're gaining. Are you just making
up for lack of dose finding in phase two or phase
one where you didn't push the dose enough to
achieve some toxicity that you can identify? So I
don't see any purpose.
DR. HUANG: Is that the Committee
recommendation?
DR. VENITZ: Only speaking for myself.
DR. WATKINS: Yes.
DR. VENITZ: Any other comments?
[No response.]
DR. VENITZ: Are you ready for the vote?
Looks like it's late.
424
Okay; then, we're voting on question
number nine, and I think we're starting with Dr.
Barrett.
DR. BARRETT: No.
DR. VENITZ: Dr. Blaschke?
DR. BLASCHKE: No.
DR. VENITZ: Dr. Capparelli?
DR. CAPPARELLI: No.
DR. VENITZ: Dr. D'Argenio?
DR. D'ARGENIO: No.
DR. VENITZ: Dr. Davidian?
DR. DAVIDIAN: Abstain.
DR. VENITZ: Dr. Derendorf?
DR. DERENDORF: No.
DR. VENITZ: Dr. Giacomini?
DR. GIACOMINI: No.
DR. VENITZ: Dr. Hall?
DR. HALL: No.
DR. VENITZ: Dr. Jusko?
DR. JUSKO: No.
DR. VENITZ: Dr. McLeod?
DR. MCLEOD: No.
425
DR. VENITZ: Dr. Sadee?
DR. SADEE: No.
DR. VENITZ: Dr. Watkins?
DR. WATKINS: No.
DR. VENITZ: It looks like I'm speaking
for the Committee, so I'm a no.
So we've got 12 noes and one abstention.
DR. HUANG: So we probably do not need to
ask about question number 10.
Originally, we were asking whether should
we consider individual factors first and then
recommend a study or after the modeling and
simulation. But since the answer is no, the only
final question, is there any other issues that we
should have been addressed in the concept paper?
We have heard comments that transporter-related
issues; we probably need an additional discussion
before we have some more general discussion, more
general recommendation or guidance.
But are there other areas where the
science is mature that we have not included in our
concept paper?
426
DR. VENITZ: Any suggestions, comments for
Dr. Huang?
DR. HALL: I notice one thing: it's not
so much something to add but maybe something to
think about taking out. You mentioned stimulation
several times, and to the best of my knowledge,
there are no examples of clinical drug interactions
due to stimulation. Maybe the guys at Merck have
some more information on that, because they've
worked on it, but that seems to be just an
unnecessary burden, I think.
DR. DERENDORF: I hope that this guidance
doesn't end up as a checklist with all kinds of
studies that are required independent of if they're
really needed or not from a response point of view.
I think each drug is different, and each
interaction has a different significance, and that
needs to be considered somewhere. And just to do a
study to do a study isn't good enough. So there
needs to be some flexibility based on the
individual drug.
DR. VENITZ: And I'd like to recommend
427
that as far as the process is concerned that
perhaps you could review with the Committee at a
future meeting not just the guidance per se but the
decision making process that is part of it, because
part of the issues that I think most of us had
wrestled with when you forced us to vote is to put
those questions in perspective, and I think some of
the votes may have gotten different results if we
had seen how that fits into the overall scheme,
such as recommendations for further process.
DR. JUSKO: Many years ago, Craig Brader
did some very nice drug interaction studies looking
at diuretics and their effects and found that it
was the drug in the urine that best represented the
biophase for the action of the diuretics and that
drug interactions, when looked at from the
viewpoint of plasma concentrations, were misleading
in terms of the clinical relevance of such
interactions.
So perhaps something could be added to the
guidance about what may be the relevant biophase
for the activity of the drug and include that in
428
the measurements in the context of drug
interactions. The whole guidance speaks to drug
interactions in the pharmacokinetic sense, and of
course, probably in the next decade, you'll be
getting to drug interactions and pharmacodynamics.
DR. VENITZ: Any further comments?
Then let me turn the podium over to Dr.
Lesko, who is going to wrap up the meeting for
today, right?
DR. LESKO: Thank you. I'll do that right
from my seat here, and I'm sure I wouldn't be very
popular if I take more than 30 seconds, given the
hour of the day, to wrap up. So I'm going to be
kind and thank the Committee that we don't need to
ask for any recounts on any of the votes.
[Laughter.]
DR. LESKO: However, the discussion today
was extremely helpful to us, and we really
appreciate your thoughtfulness and the quality of
your discussions and questions, and we left here, I
think, achieving the goals that we set out for
early this morning.
429
So I want to express your appreciation for
today and the hard work that you've done and look
forward to another exciting and high quality
discussion tomorrow on our biomarker topic that
we'll be bringing to the Committee.
DR. VENITZ: Thank you, and then, one last
announcement: the Committee members, we are going
to meet for dinner at 6:30 in the hotel restaurant
right next door, so hopefully, we will see you all.
If not, we will see you tomorrow, bright-eyed,
bushy-tailed at 8:00 for the second part of this.
[Whereupon, at 5:33 p.m., the meeting was
recessed, to reconvene on Thursday, November 4,
2004.]
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