Guidance for Industry
Pharmacokinetics in Pregnancy —
Study Design, Data Analysis,
and Impact on Dosing and Labeling
(PDF
version of this document)
DRAFT GUIDANCE
This guidance
document is being distributed for comment purposes only.
Comments and suggestions
regarding this draft document should be submitted within 60 days
of publication in the Federal Register of the notice
announcing the availability of the draft guidance. Submit
comments to the Division of Dockets Management (HFA-305), Food and
Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD
20852. All comments should be identified with the docket number
listed in the notice of availability that publishes in the
Federal Register.
For questions regarding this
draft document contact (CDER) Kathleen Uhl 301-443-5157.
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
October 2004
Clinical Pharmacology
Additional copies are available
from:
Office of Training and Communications
Division of Drug Information, HFD-240
Center for Drug Evaluation and Research
Food and Drug Administration
5600 Fishers Lane
Rockville, MD 20857
(Tel) 301-827-4573
http://www.fda.gov/cder/guidance/index.htm
Draft — Not for Implementation
TABLE OF CONTENTS
I. INTRODUCTION.
II.
BACKGROUND
III. DECIDING WHETHER TO CONDUCT A
PHARMACOKINETIC STUDY IN PREGNANT WOMEN
E. Sample Collection and
Analysis
Guidance for Industry
Pharmacokinetics in Pregnancy —
Study Design, Data Analysis, and
Impact on Dosing and Labeling
This
draft guidance, when finalized, will represent the Food and Drug
Administration’s (FDA’s) current thinking on this topic. It does
not create or confer any rights for or on any person and does not
operate to bind FDA or the public. You can use an alternative
approach if the approach satisfies the requirements of the
applicable statutes and regulations. If you want to discuss an
alternative approach, contact the FDA staff responsible for
implementing this guidance. If you cannot identify the
appropriate FDA staff, call the appropriate number listed on the
title page of this guidance.
Draft — Not for Implementation
I.
INTRODUCTION
This guidance describes a basic framework for
designing and conducting PK/PD studies in pregnant women. It
provides recommendations to sponsors on how to assess the influence
of pregnancy on the pharmacokinetics (PK), and where appropriate,
the pharmacodynamics (PD) of drugsor biologic products.
Additionally, this guidance provides recommendations to primary
investigators, clinical researchers, and clinical pharmacologists
about issues to consider when designing and conducting PK studies in
pregnant women.
The Agency recommends using this guidance in
conjunction with other FDA and ICH guidances, and pharmacological
and clinical literature, on the design, conduct, and interpretation
of pharmacokinetic studies. Because the conduct of studies in
pregnant women requires specialized knowledge in a variety of areas,
investigators designing such studies are encouraged to obtain advice
from experts in fields such as obstetrics, pediatrics, pharmacology,
clinical pharmacology, pharmacometrics, statistics, and other
applicable disciplines. Although this guidance provides
recommendations on when PK studies in pregnant women are
appropriate, it does not address ways to assess efficacy of a drug
in pregnancy or how to assess whether the drug causes adverse
pregnancy or neonatal outcomes.
FDA’s
guidance documents, including this guidance, do not establish
legally enforceable responsibilities. Instead, guidances describe
the Agency’s current thinking on a topic and should be viewed only
as recommendations, unless specific regulatory or statutory
requirements are cited. The use of the word should in Agency
guidances means that something is suggested or recommended, but not
required.
Ideally, pharmacologic agents would not be
needed during pregnancy; however, some women enter pregnancy with
medical conditions that require ongoing or episodic treatment (e.g.,
asthma, epilepsy, hypertension). During pregnancy, new medical
problems can also develop, and old ones can be exacerbated (e.g.,
migraine headaches), requiring pharmacologic therapy. Studies have
shown that most pregnant women do use either prescribed or
over-the-counter medications during pregnancy (Bonati 1990, De Vigan
1999, Lacroix 2000, Mitchell 2001). Interviews of approximately
20,000 U.S. and Canadian women conducted over 25 years reported a
mean of 2.3 medications used during pregnancy, excluding vitamins
and minerals (Mitchell 2001). Of the women interviewed, 28 percent
reported using more than four medications during pregnancy, and
medication use increased with maternal age. In addition, the mean
number of medications taken, in successive 5-year intervals,
progressively increased from 2.7 to 4.4, indicating secular patterns
of medication use by pregnant women. A comparison of therapeutic
drug use during pregnancy in Europe showed that 64 percent of women
used at least one drug during pregnancy (De Vigan 1999), while in
France, pregnant women were prescribed an average of five drugs
during the first trimester (Lacroix 2000).
Generally, the safety and efficacy of a drug
are established for a particular dosage regimen or range of dosage
regimens in late phase (Phase 3) clinical trials involving
relatively typical representatives from the target patient
population. Pregnant women are actively excluded from these trials,
and, if pregnancy does occur, the usual procedure is to discontinue
treatment and drop the patient from the study. Consequently, at the
time of a drug’s initial marketing, except for products developed to
treat conditions specific to pregnancy (e.g., oxytocics, cervical
ripening agents), there are seldom human data on the appropriate
dosage and frequency of administration during pregnancy. Even after
years of marketing, data in product labels regarding PK and dose
adjustments during pregnancy rarely provide more information for
appropriate prescribing in pregnancy than was available at the time
of initial marketing.
The few data to address appropriate dosage and
frequency of administration in pregnancy are not usually supported
by a full understanding of the alterations of the PK of the drug in
pregnancy. For example, the majority of published PK studies of
anti-infective drug products during pregnancy were conducted at the
time of abortion or delivery (usually via cesarean section) and were
done to determine the transplacental passage of drug. In the
absence of data, the usual adult dose is typically prescribed for
pregnant women. Because of the physiologic changes inherent in
pregnancy, the result can be substantial under dosing, or, in some
cases, excessive dosing.
Extrapolation of PK data from studies performed
in nonpregnant adults fails to take into account the impact of the
many physiologic changes that occur during pregnancy. Most of the
physiologic changes manifest during the first trimester and peak
during the second trimester of pregnancy. Physiologic changes are
not fixed throughout pregnancy but rather reflect a continuum of
change as pregnancy progresses, with return to baseline at various
rates in the postpartum period. The physiologic changes have the
potential to alter the PK and/or PD of drugs. Some of these changes
include:
·
Changes in total body weight and body fat
composition.
·
Delayed gastric emptying and prolonged
gastrointestinal transit time.
·
Increase in extra cellular fluid and total body water.
·
Increased cardiac output, increased stroke volume, and
elevated maternal heart rate.
·
Decreased albumin concentration with reduced protein
binding.
·
Increased blood flow to the various organs (e.g.,
kidneys, uterus).
·
Increased glomerular filtration rate.
·
Changed hepatic enzyme activity, including phase I
CYP450 metabolic pathways (e.g., increased CYP2D6 activity),
xanthine oxidase, and phase II metabolic pathways (e.g., N-acetyltransferase).
A significant amount of pharmacologic research
has been conducted to improve the quality and quantity of data
available for other altered physiologic states (e.g., in patients
with renal and hepatic disease) and for other patient subpopulations
(e.g., pediatric patients).
The need for PK/PD studies in pregnancy is no less than for these
populations, nor is the need for the development of therapeutic
treatments for pregnant women.
Ethical issues are important when considering
studying drugs in pregnant women. Given the large number of
pregnant women who need prescription medicines to maintain their
health, some have argued that it is unethical not to obtain
dosing information in this subpopulation (Faden 2000). Others
recommend that only pregnant women who need a drug for therapeutic
reasons be included in clinical studies, citing that drug studies
cannot be done in “normal pregnant volunteers” (Stika 2001).
All studies in pregnant women must
conform to all applicable regulations, including human subject
protection.
The Agency recommends that all studies in pregnant women have
Institutional Review Board (IRB) review and informed consent for all
study participants.
Pregnant women may be involved in PK studies
if the following conditions are met (45 CFR Subpart B 46.204):
·
Preclinical studies, including studies on pregnant
animals, and clinical studies, including studies on nonpregnant
women, have been conducted and provide data for assessing potential
risk to pregnant women and fetuses; and
·
The risk to the fetus is not greater than minimal and
the purpose of the research is the development of important
biomedical knowledge which cannot be obtained by any other means.
The definition of minimal risk is broad.
The fetal risk is considered minimal when the estimated risk to the
fetus is no more than that from established procedures routinely
used in an uncomplicated pregnancy or in a pregnancy with
complications comparable to those being studied.
Although PK studies in
pregnancy can be considered in Phase 3 development programs
depending on anticipated use in pregnancy and the results of
reproductive toxicity studies, the FDA anticipates that most PK
studies in pregnant women will occur in the postmarketing period and
will be conducted using pregnant women who have already been
prescribed the drug as therapy by their own physician. An example
of a minimal risk study would be one to determine PK/PD of an
antihypertensive medication in pregnant women who are taking that
medication to treat hypertension during pregnancy. The decision to
use the antihypertensive medication is made by the patient and her
physician independent of participation in the PK/PD study.
Information on human pregnancy experiences
and exposures will emerge during the postmarketing phase for
virtually all drug products. Sponsors are requested to explicitly
address positive or negative experiences during pregnancy or
lactation as one of the safety issues in the Overall Safety
Evaluation section of the Periodic Safety Update Report.
This source of information is
valuable in determining whether to conduct PK studies in pregnant
women. Other important sources of information include publications
concerning safety (e.g., reports that describe the use of the drug
in pregnancy) or efficacy in pregnancy and information from medical
specialty groups. These types of postmarketing exposure and safety
data on drug products provide the basis for determining the need for
PK assessment of a drug in pregnant women.
This guidance recommends that PK studies be
conducted in pregnant women
in any of the following situations:
·
The drug is known
to be prescribed in or used by pregnant women, especially in the
second and third trimesters.
·
For a new drug or indication, if there is anticipated
or actual use of the drug in pregnancy.
·
Use is expected
to be rare, but the consequences of uninformed dosages are great
(e.g., narrow therapeutic range drugs, cancer chemotherapy). Drugs
of this type can normally be studied in pregnant patients.
·
Pregnancy is likely to alter significantly the PK of a
drug (e.g., renally excreted drug) and any of the above apply.
PK studies in pregnant women are not
recommended if the drug is not used in pregnant women or the drug
has known or highly suspect fetal risk.
For approved products, consider whether
a study in pregnant women must be conducted under the
investigational new drug (IND) regulations (21 CFR 312.2). If there
is a concern for significantly increasing the risk (or decreasing
the acceptability of the risks) in a patient population (i.e., the
mother or fetus), an IND would be needed (21 CFR 312.2(b)(iii)).
Also, according to the IND regulations, if a different route of
administration or dosage level is used, an IND would be needed.
A
population PK approach with nonlinear mixed effects modeling
techniques can be used as an alternate way to enroll pregnant women
in PK studies and minimize the number of blood draws and PD
assessments. The population PK approach can assess the impact on
the PK of a drug on various covariates, such as maternal
characteristics (e.g., age, gravity, parity, race, weeks or
trimester of gestation), concomitant medications, and underlying
medical conditions. For example, a measure of pregnancy status such
as weeks gestation can be one of the covariates, making it possible
to model the relationship between gestational age of pregnancy and
PK parameters such as the apparent clearance of the drug (CL/F).
In
principle, a population PK study design and analysis might detect PK
differences large enough to warrant dosage adjustment if the study
has enough pregnant and nonpregnant women enrolled with sufficient
representation of second and third trimesters (with a continuum of
gestational ages from 13 to 40 weeks). Typically, each patient is
only sparsely sampled to obtain plasma drug concentration data
and/or PD data. Due to the intrinsic characteristics of a
population PK study, the controls for this study design can differ
from other study designs and can potentially include matched healthy
nonpregnant female volunteers. To ensure the ability to determine
the inter-occasion variability and prevent a parallel group trial
design, a cohort of study subjects would have data collected from
all trimesters and the postpartum period. Considering the number of
subjects in the study and the key objective of the study, efforts
can be made to reduce the number of influential covariates such as
concomitant medication.
Some
investigators have proposed conducting a population PK study as a
preliminary step and to subsequently conduct a standard intensive PK/PD
study if the population PK study suggests changes between the
pregnant and nonpregnant women (Stika 2000). For further
information about the population PK approach, see the
Guidance for Industry Population Pharmacokinetics.
The objective and design of a study are
determining factors in deciding adequate sample size. The number of
subjects enrolled in a study should be sufficient to detect PK
differences large enough to warrant dosage adjustments. Sample size
considerations include PK and PD variability for the drug being
studied, the study design (i.e., single-dose versus multiple-dose),
and the physiologic changes inherent in pregnancy. For a population
PK approach,
sparse sampling with a larger number of subjects that span the
gestational time periods of interest is encouraged.
As a practical matter, it is prudent that the
final number of subjects enrolled be in excess of that originally
determined by standard sample size calculations to take into account
withdrawal of subjects from the study. Even if data for a subject
are missing for one trimester, the Agency suggests that the subject
be retained in the study for the postpartum assessments.
In
single-dose studies, the same dose can usually be administered to
all women in the study. Lower or less frequent doses can be
considered to minimize fetal risk in pregnant women who volunteer to
take the medication for study purposes, even if it is expected to
pose minimal risk at standard doses. The dosage regimen can be
adjusted based on the best available pre-study estimates of the PK
of the drug and its active metabolites and what is known about drug
elimination. A concentration-controlled study design or a dosage
adjustment based on the patient’s response are alternative methods
to consider. For example, the study might be conducted to achieve a
specific target concentration using therapeutic drug monitoring
procedures. When studying pregnant patients who need the study
drug, the dose can be modified, either increased or decreased as
pregnancy progresses, to achieve the appropriate response (e.g.,
lowering of blood pressure, or to decrease adverse events such as
hypotensive episodes with antihypertensive therapy).
E. Sample
Collection and Analysis
The Agency recommends that plasma
or whole blood samples and urine samples
be analyzed for the
parent drug and any metabolites with known or suspected activity,
therapeutic or adverse. It is recommended that the frequency and
duration of plasma sampling and urine collection be sufficient to
estimate accurately the relevant PK parameters for the parent drug
and its active metabolites (see Section VI, Data Analysis).
Plasma
protein binding, like renal function, is often altered in pregnancy.
For example, albumin and alpha-1-acid glycoprotein levels are
reduced in pregnancy, consequently the protein binding of drugs can
be affected. With systemically active drugs and metabolites, the
unbound concentrations are generally believed to determine the rate
and extent of delivery to the sites of action. For drugs and
metabolites with a relatively low extent of plasma protein binding
(e.g., the extent of binding is less than 80 percent), alterations
in binding due to pregnancy are small in relative terms. In such
cases, description and analysis of the PK in terms of total
concentrations would be sufficient. For drugs where the extent of
protein binding is greater than 80 percent, primarily to albumin, it
is recommended that the PK be described and analyzed with respect to
the unbound concentrations of the drug and active metabolites.
Although unbound concentrations should be measured in each plasma
sample, if the binding is concentration-independent and unaffected
by metabolites or other time-varying factors, the fraction unbound
can be determined using a limited number of samples or even a single
sample from each patient during each trimester. The unbound
concentration in each sample should then be estimated by multiplying
the total concentration by the fraction unbound for the individual
patient.
It is possible to study drugs that have no
intended direct therapeutic benefit to the pregnant woman provided
that the risk to the fetus is minimal (45 CFR 46). For example,
probe substrates can be used to investigate drug metabolism (e.g.,
cytochrome P-450 activity) or drug transporter status (e.g.,
p-glycoprotein). Data from these studies offer generalizable
information to other pregnant women but do not offer direct
therapeutic benefit to study participants. The Agency encourages
sponsors or investigators to explore additional safeguards for human
subject protection for this type of study. To minimize exposure to
a nontherapeutic drug, each pregnant woman can be exposed to the
drug once during pregnancy and in the postpartum period employing a
nonlongitudinal design (e.g., one cohort of women sampled in second
trimester and postpartum and another cohort of women sampled in
third trimester and postpartum). Examples of additional safeguards
include administering only products with a long or known record of
safety in pregnancy, administering products using only a single dose
of the drug, using lower doses of the drug, decreasing the number of
drugs (probe substrates) used in any study subject, and limiting
study participants to pregnant women only in second or third
trimester.
PK studies are usually enhanced by including
PD assessments as part of the study. The Agency encourages sponsors
to discuss the selection of the PD endpoints with the appropriate
FDA review staff. Endpoints would be based on the pharmacological
characteristics of the drug and metabolites (e.g., the behavior of
other drugs in the same pharmacological class), and include
consideration of relevant biomarkers.
Fetal PD endpoints can warrant study as well (e.g., fetal heart rate
and rhythm response to maternal administration of an antiarrhythmic
drug).
The
primary intent of the data analysis is to assess whether dosage
adjustment is needed for pregnant patients, and, if so, to develop
dosing recommendations for such patients based on gestational age or
trimester. The analysis, specifically modeling and dosing
recommendations, will depend on the study design characteristics.
The categorization of pregnancy status, either as nominal (e.g.,
trimester) or continuous (e.g., week of gestation) data will direct
the type of analysis performed. The Agency encourages giving
special analytical considerations to longitudinal study designs and
the baseline (e.g., postpartum) comparisons. The data analysis
typically consists of the following steps:
·
Estimation of PK
parameters
·
Development of
dosing recommendations
The Agency
recommends that total and unbound plasma concentration data (and
urinary excretion data if collected) be used to estimate PK
parameters of the parent drug and metabolite(s). Standard PK
parameters of a drug include the area under the plasma concentration
curve (AUC), peak concentration (Cmax), plasma clearance
(CLT) or apparent oral clearance (CL/F), renal clearance
(CLR), apparent volume of distribution (VZ/F
or Vss/F), and terminal half-life (t1/2). It
is recommended that PK parameters be expressed in terms of total and
unbound concentrations and when applicable (e.g., oral and renal
clearance, expressed in terms of body weight, L/hr/kg). For drugs
and metabolites with a relatively low extent of plasma protein
binding (e.g., extent of binding less than 80 percent), description
and analysis of the PK in terms of total concentrations can be
sufficient. Noncompartmental and/or compartmental modeling
approaches to parameter estimation can be employed.
Specific
dosing recommendations should be constructed based on study
results. Typically the dose should be adjusted to produce a
comparable range of unbound plasma concentrations of drug or active
metabolites in both controls and pregnant patients. Simulations are
encouraged as a means to identify doses and dosing intervals that
achieve that goal for pregnant patients at different trimesters or
gestational ages.
One
approach might be for the sponsor to recommend, prior to the conduct
of the studies, specific no effect boundaries for the ratio
of a PK measurement from pregnant patients and controls, such as (AUCu,pregnant/AUCu,control)
or (Dpregnant/Dcontrol). If the 90 percent confidence interval for
the ratio of PK measurements falls within these boundaries, the
sponsor might claim no effect of pregnancy on PK, and it
would be reasonable to conclude that no dosage adjustment is needed
for pregnancy. The sponsor might determine no effect
boundaries from population or individual PK/PD relationships,
dose-finding studies and/or dose-response studies which are
conducted as part of drug development.
Another
approach might be for the sponsor to assume no effect
boundaries of 80-125 percent for Cmax
and AUC without further justification, recognizing that the small
sample sizes in pregnancy studies coupled with high intersubject
variability can preclude meeting the 80-125 percent no effect
boundaries.
For some
drugs, pregnancy may not alter PK sufficiently to warrant dosage
adjustment. A sponsor might make this claim by providing an
analysis of the study data to show that the PK measurements most
relevant to therapeutic outcome in pregnant patients are similar or
equivalent to those in the comparator group.
The Agency
recommends that labeling reflect the data from PK/PD studies in
pregnancy and, if known, dosing recommendations during pregnancy.
The labeling would reflect the data pertaining to the effect of
pregnancy on the PK and PD obtained from studies conducted. If no
studies were conducted, the Agency recommends that the labeling
indicate that the impact of pregnancy was not studied. If
the PK/PD is altered during pregnancy, the appropriate description
of such and recommendations for dosing should be stated in
labeling.
The
various permutations of intrinsic drug characteristics and the
effect of pregnancy on drug performance preclude precise
specification of how such drugs would be labeled. The following
comments offer general suggestions on labeling.
It is recommended that this section include
information pertinent to pregnancy such as:
·
Disposition of
parent drug and metabolites, if applicable
·
Effects of
pregnancy on protein binding of parent drug and metabolites, if
applicable
·
Effects of
changes in urinary pH or other special situations (e.g., tubular
secretion inhibited by probenecid)
It is
recommended that this section recapitulate, in brief, the PK changes
found in pregnancy and, if needed, dosing adjustments for pregnant
patients. This information should be based on the studies performed
as described in this guidance. Reference should be made to the
PRECAUTIONS/PREGNANCY and the DOSAGE AND ADMINISTRATION sections.
The following text provides examples of possible wording for these
sections.
The
simplest situation involves drugs for which pregnancy has little or
no effect on PK:
The disposition of [Drug X]
was studied in [number of] pregnant patients [in y trimester or from
a through b weeks gestation]. Pregnancy has little or no influence
on [Drug X] pharmacokinetics and no dosing adjustment is
needed.
This
should be followed by a brief summary of the PK/PD data (e.g., mean,
range).
Similarly,
for drugs whose PK is influenced by pregnancy, the statement similar
to the following can be modified as appropriate and in accordance
with what is known about the drug (e.g., active or toxic metabolite)
and from the studies performed in accordance with this guidance:
The disposition of [Drug X]
was studied in [number of] pregnant patients [in y trimester or from
a through b weeks gestation]. Elimination of the drug (and
metabolite, if applicable) is significantly changed during
pregnancy. Total body clearance of (unbound, if applicable)
[Drug X]/metabolite was reduced/increased in pregnant patients
compared to [healthy postpartum women, the same women prior to
pregnancy or c weeks postpartum]. The terminal half-life of
[Drug X]/metabolite is [prolonged/decreased] by Y-, and Z- fold
in second and third trimesters, respectively. Protein binding of
[Drug X]/metabolite [is/is not] affected by pregnancy. The
[drug/metabolite accumulates/does not accumulate] in pregnant
patients on chronic administration resulting in increased/decreased
plasma levels of drug/metabolite. The pharmacologic response [is/is
not] affected by pregnancy. The dosage/dosing interval should be
[decreased/increased] in pregnant patients receiving [Drug X]
(see DOSAGE AND ADMINISTRATION).
In
addition to standard labeling for use in pregnancy, including
Pregnancy Category, a brief statement regarding PK/PD in pregnancy
would be included in the PRECAUTIONS/PREGNANCY section with cross
reference to DOSAGE AND ADMINISTRATION and CLINICAL PHARMACOLOGY
sections. If PK studies in pregnancy were not conducted, the Agency
recommends that the labeling indicate that.
As
appropriate, the following information could be included:
·
A statement
describing the relationship between the drug’s clearance and
pregnancy
·
A statement
describing how the dose would be adjusted during pregnancy, for
example:
The dose of [Drug X]
should be [increased/decreased by _____%] during pregnancy.
·
A statement
describing how the dose would be adjusted in the postpartum time
period in nonlactating women, specifying the time period studied
(e.g., 2 weeks postpartum)
·
The dosing
adjustment regimen can alternatively be represented in tabular
format, for example:
Group |
Dosage (mg) |
Frequency |
1st trimester |
x |
Every y hours |
2nd trimester |
|
|
3rd trimester |
|
|
Postpartum
(specify time) |
|
|
Standard adult dose |
|
|
The influence of pregnancy on
[Drug X]
pharmacokinetics is sufficiently small that no dosing adjustment is
needed.
Bonati, M, R Bortulus, F
Marchetti, M Romero, and G Tognoni, 1990, Drug Use in
Pregnancy: An Overview of
Epidemiological (Drug Utilization) Studies, Eur J Clin Pharmacol,
38:325-8.
De Vigan, C, HEK De Walle, S Cordier
et al., 1999, Therapeutic Drug Use During Pregnancy: A Comparison
in Four European Countries, J Clin Epidemiol, 52(10):977-82.
Faden, R, 2000, Ethics of Studying
Pregnant Women, FDA/NICHD Conference: Clinical Pharmacology During
Pregnancy: Addressing Clinical Needs Through Science, Internet:
http://www.fda.gov/cder/present/clinpharm2000/1205preg.txt.
Lacroix, I, C Damase-Michel, M
Lapeyre-Mestre, and JL Montastruc, 2000, Prescription of Drugs
During Pregnancy in France, Lancet, 356:1735-6.
Little, BB, 1999, Pharmacokinetics
During Pregnancy: Evidence-Based Maternal Dose Formulation, Obstet
Gynecol, 93:858-68.
Mitchell, AA, S Hernández-Díaz, C
Louik, and MM Werler, 2001, Medication Use in Pregnancy,
Pharmacoepidemiology and Drug Safety,10:S146.
Prevost, RR, SA Akl, WD Whybrew, and
B Sibai, 1992, Oral Nifedipine Pharmacokinetics in Pregnancy-induced
Hypertension, Pharmacother, 12:174-177.
Reynolds, F, 1991, Pharmacokinetics,
In: Hytten, F and G Chamberlain (editors), Clinical Physiology in
Obstetrics, Boston, MA: Blackwell Scientific Publications,
224-240.
Stika, CE, 2000, Industry
Experience: Design and Conduct of a Pregnancy PK Study, FDA/NICHD
Conference: Clinical Pharmacology During Pregnancy: Addressing
Clinical Needs Through Science, Internet: http://www.fda.gov/cder/present/clinpharm2000/Stika/index.htm.
Stika, CE and MC Frederiksen, 2001, Drug Therapy in Pregnant and
Nursing Women, In:
Atkinson, AJ Jr., CE Daniels, RL Dedrick et al.
(editors), Principles of
Clinical Pharmacology, New York: Academic Press, 277-291.
Wadelius, M, E Darj, G Frenne, and A
Rane, 1997, Induction of CYP2D6 in Pregnancy, Clin Pharmacol Ther,
62:400-7.
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Date created: 10/29/04 |