Guidance for Industry
Estimating the Maximum Safe Starting Dose in Initial Clinical Trials
for Therapeutics in Adult Healthy Volunteers
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Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
July 2005
Pharmacology and Toxicology
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U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
July 2005
Pharmacology and Toxicology
Guidance for Industry
Estimating the Maximum Safe
Starting Dose in Initial Clinical Trials for Therapeutics in Adult
Healthy Volunteers
This
guidance represents 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.
This guidance outlines a process (algorithm)
and vocabulary for deriving the maximum recommended starting dose
(MRSD) for first-in-human clinical trials of new molecular
entities in adult healthy volunteers, and recommends a
standardized process by which the MRSD can be selected. The
purpose of this process is to ensure the safety of the human
volunteers.
The goals of this guidance are to: (1)
establish a consistent terminology for discussing the starting
dose; (2) provide common conversion factors for deriving a human
equivalent dose (HED); and (3) delineate a strategy for selecting
the MRSD for adult healthy volunteers, regardless of the projected
clinical use. This process is depicted in a flow chart that
presents the decisions and calculations used to generate the MRSD
from animal data (see Appendix E).
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.
The process
identified in this guidance pertains to determining the MRSD for
adult healthy subjects when beginning a clinical investigation of
any new drug or biological therapeutic that has been studied in
animals. This guidance is not pertinent to endogenous hormones
and proteins (e.g., recombinant clotting factors) used at
physiologic concentrations or prophylactic vaccines. The process
outlined in this guidance pertains primarily to drug products for
which systemic exposure is intended; it does not address dose
escalation or maximum allowable doses in clinical trials.
Although the
process outlined in this guidance uses administered doses,
observed toxicities, and an algorithmic approach to calculate the
MRSD, an alternative approach could be proposed that places
primary emphasis on animal pharmacokinetics and modeling rather
than dose (Mahmood et al. 2003; Reigner and Blesch 2002). In
a limited number of cases, animal pharmacokinetic data can be
useful in determining initial clinical doses.
However, in the majority of investigational new drug applications
(INDs), animal data are not available in
sufficient detail to construct a scientifically valid,
pharmacokinetic model whose aim is to accurately project an MRSD.
Toxicity should be avoided at the initial
clinical dose. However, doses should be chosen that allow
reasonably rapid attainment of the phase 1 trial objectives (e.g.,
assessment of the therapeutic’s tolerability, pharmacodynamic or
pharmacokinetic profile). All of the relevant preclinical data,
including information on the pharmacologically active dose, the
full toxicologic profile of the compound, and the pharmacokinetics
(absorption, distribution, metabolism, and excretion) of the
therapeutic, should be considered when determining the MRSD.
Starting with doses lower than the MRSD is always an option and
can be particularly appropriate to meet some clinical trial
objectives.
The remainder of this
guidance focuses on the recommended algorithmic process for
starting dose extrapolation from animals to humans based on
administered doses, since this method will likely be useful for
the majority of INDs seeking to investigate new drugs in healthy
volunteers. Some classes of drugs (e.g., many cytotoxic or
biological agents) are commonly introduced into initial clinical
trials in patient volunteers rather than healthy volunteers.
Typically, patients are used instead of healthy volunteers when a
drug is suspected or known to be unavoidably toxic. This guidance
does not address starting doses in patients. However, many
principles and some approaches recommended here may be applicable
to designing such trials.
The recommended process for selecting the
MRSD is presented in Appendix E and described in this section.
The major elements (i.e., the determination of the no observed
adverse effect levels (NOAELs) in the tested animal species,
conversion of NOAELs to HED, selection of the most appropriate
animal species, and application of a safety factor) are all
discussed in greater detail in subsequent sections. Situations
are also discussed in which the algorithm should be modified. The
algorithm is intended to be used for systemically administered
therapeutics. Topical, intranasal, intratissue, and compartmental
administration routes and depot formulations can have additional
considerations, but similar principles should apply.
The process of calculating the
MRSD should begin after the toxicity data have been analyzed.
Although only the NOAEL should be used directly in the algorithm
for calculating an MRSD, other data (exposure/toxicity
relationships, pharmacologic data, or prior clinical experience
with related drugs) can affect the choice of most appropriate
species, scaling, and safety factors.
The NOAEL for each species tested
should be identified, and then converted to the HED using
appropriate scaling factors. For most systemically administered
therapeutics, this conversion should be based on the normalization
of doses to body surface area. Although body surface area
conversion is the standard way to approximate equivalent exposure
if no further information is available, in some cases
extrapolating doses based on other parameters may be more
appropriate. This decision should be based on the data available
for the individual case. The body surface area normalization and
the extrapolation of the animal dose to human dose should be done
in one step by dividing the NOAEL in each of the animal species
studied by the appropriate body surface area conversion factor (BSA-CF).
This conversion factor is a unitless number that converts mg/kg
dose for each animal species to the mg/kg dose in humans, which is
equivalent to the animal’s NOAEL on a mg/m2 basis. The
resulting figure is called a human equivalent dose (HED). The
species that generates the lowest HED is called the most sensitive
species.
When information indicates that a
particular species is more relevant for assessing human risk (and
deemed the most appropriate species), the HED for that
species may be used in subsequent calculations, regardless of
whether this species is the most sensitive. This situation is
more applicable to biologic therapies, many of which have high
selectivity for binding to human target proteins and limited
reactivity in species commonly used for toxicity testing. In such
cases, in vitro binding and functional studies should be conducted
to select an appropriate, relevant species before toxicity studies
are designed (refer to ICH guidance for industry S6 Preclinical
Safety Evaluation of Biotechnology-Derived Pharmaceuticals for
more details).
(However, if serious toxicities are observed in an animal species
considered less relevant, those toxicities should be taken into
consideration in determining the species to be used to calculate
an HED. For example, in one particular case, dog was selected as
the animal species used for calculation of an HED because of
unmonitorable cardiac lesions, even though the rat was considered
the most relevant species based on pharmacological activity
data.) Additionally, a species might be considered an
inappropriate toxicity model for a given drug if the dose-limiting
toxicity in that species was concluded to be of limited value for
human risk assessment, based on historical comparisons of
toxicities in the animal species to those in humans across a
therapeutic class (i.e., the dose-limiting toxicity is
species-specific). In this case, data from that species should
not be used to derive the HED. Without any additional information
to guide the choice of the most appropriate species for assessing
human risk, the most sensitive species is designated the most
appropriate, because using the lowest HED would generate the
most conservative starting dose.
A safety factor should then be
applied to the HED to increase assurance that the first dose in
humans will not cause adverse effects. The use of the safety
factor should be based on the possibility that humans may be more
sensitive to the toxic effects of a therapeutic agent than
predicted by the animal models, that bioavailability may vary
across species, and that the models tested do not evaluate all
possible human toxicities. For example, ocular disturbances or
pain (e.g., severe headaches) in humans can be significant
dose-limiting toxicities that may go undetected in animal
studies.
In general, one should consider using a
safety factor of at least 10. The MRSD should be obtained by
dividing the HED by the safety factor. Safety concerns or design
shortcomings noted in animal studies may increase the safety
factor, and thus reduce the MRSD further. Alternatively,
information about the pharmacologic class (well-characterized
classes of therapeutics with extensive human clinical and
preclinical experience) may allay concerns and form the basis for
reducing the magnitude of the default safety factor and increasing
the MRSD. Although a dose lower than the MRSD can be used as the
actual starting dose, the process described in this guidance will
derive the maximum recommended starting dose. This algorithm
generates an MRSD in units of mg/kg, a common method of dosing
used in phase 1 trials, but the equations and conversion factors
provided in this guidance (Table 1, second column) can be used to
generate final dosing units in the mg/m2 form if
desired.
As previously stated, for purposes of initial
clinical trials in adult healthy volunteers, the HED should
ordinarily be calculated from the animal NOAEL. If the HED is
based on an alternative index of effect, such as the
pharmacologically active dose (PAD), this exception should be
prominently stipulated in descriptions of starting dose
calculations.
The remainder of this guidance
provides a description of the individual steps in the recommended
process and the reasoning behind each step.
The first step in determining the
MRSD is to review and evaluate the available animal data so that a
NOAEL can be determined for each study. Several definitions of
NOAEL exist, but for selecting a starting dose, the following is
used: the highest dose level that does not produce a significant
increase in adverse effects in comparison to the control group.
In this context, adverse effects that are biologically significant
(even if they are not statistically significant) should be
considered in the determination of the NOAEL. The NOAEL is a
generally accepted benchmark for safety when derived from
appropriate animal studies and can serve as the starting point for
determining a reasonably safe starting dose of a new therapeutic
in healthy (or asymptomatic) human volunteers.
The NOAEL is not the same as the
no observed effect level (NOEL), which refers to any
effect, not just an adverse one, although in some cases the two
might be identical. The definition of the NOAEL, in contrast to
that of the NOEL, reflects the view that some effects observed in
the animal may be acceptable pharmacodynamic actions of the
therapeutic and may not raise a safety concern. The NOAEL should
also not be confused with lowest observed adverse effect level
(LOAEL) or maximum tolerated dose (MTD).
Both of the latter concepts are based on findings of adverse
effects and are not generally used as benchmarks for establishing
safe starting doses in adult healthy volunteers. (The term
level refers to dose or dosage, generally expressed as mg/kg
or mg/kg/day.)
Initial IND submissions for
first-in-human studies by definition lack
in vivo
human data or formal allometric
comparison of pharmacokinetics. Measurements of systemic levels
or exposure (i.e., AUC or Cmax)
cannot be employed for setting a safe starting dose in humans, and
it is critical to rely on dose and observed toxic response data
from adequate and well-conducted toxicology studies. However,
there are cases where nonclinical data on bioavailability,
metabolite profile, and plasma drug levels associated with
toxicity may influence the choice of the NOAEL. One such case is
when saturation of drug absorption occurs at a dose that produces
no toxicity. In this instance, the lowest saturating dose, not
the highest (nontoxic) dose, should be used for calculating the
HED.
There are essentially three types of findings
in nonclinical toxicology studies that can be used to determine
the NOAEL: (1) overt toxicity (e.g., clinical signs,
macro- and microscopic lesions); (2) surrogate markers of toxicity
(e.g., serum liver enzyme levels); and (3) exaggerated
pharmacodynamic effects. Although the nature and extent of
adverse effects can vary greatly with different types of
therapeutics, and it is anticipated that in many instances,
experts will disagree on the characterization of effects as being
adverse or not, the use of NOAEL as a benchmark for dose-setting
in healthy volunteers should be acceptable to all responsible
investigators. As a general rule, an adverse effect observed in
nonclinical toxicology studies used to define a NOAEL for the
purpose of dose-setting should be based on an effect that would be
unacceptable if produced by the initial dose of a therapeutic in a
phase 1 clinical trial conducted in adult healthy volunteers.
After the NOAELs in the relevant animal
studies have been determined, they are converted to HEDs. A
decision should be made regarding the most appropriate method for
extrapolating the animal dose to the equivalent human dose. Toxic
endpoints for therapeutics administered systemically to animals,
such as the MTD, are usually assumed to scale well between species
when doses are normalized to body surface area (i.e., mg/m2)
(EPA 1992; Lowe and Davis 1998). The basis for this assumption
lies primarily with the work of Freireich et al. (1966) and Schein
et al. (1970). These investigators reported that, for
antineoplastic drugs, doses lethal to 10 percent of rodents (LD10s)
and MTDs in nonrodents both correlated with the human MTD when the
doses were normalized to the same administration schedule and
expressed as mg/m2. Despite the subsequent analyses
showing that the MTDs for this set of drugs scale best between
species when doses are normalized to W0.75 rather than
W0.67 (inherent in body surface area normalization)
(Travis and White 1988; Watanabe et al. 1992), normalization to
body surface area has remained a widespread practice for
estimating an HED based on an animal dose.
An analysis of the affect of the allometric
exponent on the conversion of an animal dose to the HED was
conducted (see Appendix A). Based on this analysis and on the
fact that correcting for body surface area increases clinical
trial safety by resulting in a more conservative starting dose
estimate, it was concluded that the approach of converting NOAEL
doses to an HED based on body surface area correction factors (i.e.,
W0.67) should be maintained for selecting starting
doses for initial studies in adult healthy volunteers.
Nonetheless, use of a different dose normalization approach, such
as directly equating the human dose to the NOAEL in mg/kg, may be
appropriate in some circumstances. Deviations from the body
surface area approach, when describing the conversion of animal
dose to HED, should be justified. The basis for justifying direct
mg/kg conversion and examples in which other normalization methods
are appropriate are described in the following subsection.
Although normalization to body surface area
is an appropriate method for extrapolating doses between species,
consistent factors for converting doses from mg/kg to mg/m2
have not always been used. Given that body surface area
normalization provides a reasonable approach for estimating an HED,
the factors used for converting doses for each species should be
standardized. Since body surface area varies with W0.67,
the conversion factors are dependent on the weight of the animals
in the studies. However, analyses conducted to address the effect
of body weight on the actual BSA-CF demonstrated that a standard
factor provides a reasonable estimate of the HED over a broad
range of human and animal weights (see Appendix B). The
conversion factors and divisors shown in Table 1 are therefore
recommended as the standard values to be used for interspecies
dose conversions for NOAELs. (These factors may also be applied
when comparing safety margins for other toxicity endpoints (e.g.,
reproductive toxicity and carcinogenicity) when other data for
comparison (i.e., AUCs) are unavailable or are otherwise
inappropriate for comparison.)
Table 1: Conversion of Animal Doses to Human Equivalent
Doses Based on Body Surface Area |
|
|
To Convert Animal Dose in mg/kg to HEDa in mg/kg,
Either: |
Species |
Divide
Animal Dose By
|
Multiply
Animal Dose By
|
Human |
37 |
--- |
--- |
Child (20
kg)b |
25 |
--- |
--- |
Mouse |
3 |
12.3 |
0.08 |
Hamster |
5 |
7.4 |
0.13 |
Rat |
6 |
6.2 |
0.16 |
Ferret |
7 |
5.3 |
0.19 |
Guinea pig |
8 |
4.6 |
0.22 |
Rabbit |
12 |
3.1 |
0.32 |
Dog |
20 |
1.8 |
0.54 |
Primates: |
|
|
|
Monkeysc |
12 |
3.1 |
0.32 |
Marmoset |
6 |
6.2 |
0.16 |
Squirrel monkey |
7 |
5.3 |
0.19 |
Baboon |
20 |
1.8 |
0.54 |
Micro-pig |
27 |
1.4 |
0.73 |
Mini-pig |
35 |
1.1 |
0.95 |
|
|
|
|
|
a Assumes 60 kg human.
For species not listed or for weights outside the standard ranges,
HED can be calculated from the following formula:
HED = animal dose in mg/kg x
(animal weight in kg/human weight in kg)0.33.
b
This km value is provided for reference only since healthy
children will rarely be volunteers for phase 1 trials.
c
For example, cynomolgus, rhesus,
and stumptail.
The factors in Table 1 for scaling animal
NOAEL to HEDs are based on the assumption that doses scale 1:1
between species when normalized to body surface area. However,
there are occasions for which scaling based on body weight (i.e.,
setting the HED (mg/kg) = NOAEL (mg/kg)) may be more appropriate.
To consider mg/kg scaling for a therapeutic, the available data
should show that the NOAEL occurs at a similar mg/kg dose across
species. The following circumstances should exist before
extrapolating to the HED on a mg/kg basis rather than using the
mg/m2 approach. Note that mg/kg scaling will give a
twelve-, six-, and twofold higher HED than the default mg/m2
approach for mice, rats, and dogs, respectively. If these
circumstances do not exist, the mg/m2 scaling approach
for determining the HED should be followed as it will lead to a
safer MRSD.
1.
NOAELs occur at a similar mg/kg dose across test species
(for the studies with a given dosing regimen relevant to the
proposed initial clinical trial). (However, it should be noted
that similar NOAELs on a mg/kg basis can be obtained across
species because of differences in bioavailability alone.)
2.
If only two NOAELs from toxicology studies in separate
species are available, one of the following should also be true:
·
The therapeutic is administered orally and the dose
is limited by local toxicities. Gastrointestinal (GI) compartment
weight scales by W0.94 (Mordenti 1986). GI volume
determines the concentration of the therapeutic in the GI tract.
It is then reasonable that the toxicity of the therapeutic would
scale by mg/kg (W1.0).
·
The toxicity in humans (for a particular class) is
dependent on an exposure parameter that is highly correlated
across species with dose on a mg/kg basis. For example,
complement activation by systemically administered antisense
oligonucleotides in humans is believed to be dependent upon Cmax
(Geary et al. 1997). For some antisense drugs, the Cmax
correlates across nonclinical species with mg/kg dose and in such
instances mg/kg scaling would be justified.
·
Other pharmacologic and toxicologic endpoints also
scale between species by mg/kg for the therapeutic. Examples of
such endpoints include the MTD, lowest lethal dose, and the
pharmacologically active dose.
·
There is a robust correlation between plasma drug
levels (Cmax and
AUC) and dose in mg/kg.
Scaling between species based on mg/m2
is not recommended for the following categories of therapeutics:
1.
Therapeutics administered by alternative routes (e.g.,
topical, intranasal, subcutaneous, intramuscular) for which the
dose is limited by local toxicities. Such therapeutics should be
normalized to concentration (e.g., mg/area of application) or
amount of drug (mg) at the application site.
2.
Therapeutics administered into anatomical compartments that
have little subsequent distribution outside of the compartment.
Examples are intrathecal, intravesical, intraocular, or
intrapleural administration. Such therapeutics should be
normalized between species according to the compartmental volumes
and concentrations of the therapeutic.
3.
Proteins administered intravascularly with Mr >
100,000 daltons. Such therapeutics should be normalized to mg/kg.
After the HEDs have been determined from the
NOAELs from all toxicology studies relevant to the proposed human
trial, the next step is to pick one HED for subsequent derivation
of the MRSD. This HED should be chosen from the most appropriate
species. In the absence of data on species relevance, a default
position is that the most appropriate species for deriving the
MRSD for a trial in adult healthy volunteers is the most sensitive
species (i.e., the species in which the lowest HED can be
identified).
Factors that could influence the choice of
the most appropriate species rather than the default to the most
sensitive species include: (1) differences in the absorption,
distribution, metabolism, and excretion (ADME) of the therapeutic
between the species, and (2) class experience that may indicate a
particular animal model is more predictive of human toxicity.
Selection of the most appropriate species for certain biological
products (e.g., human proteins) involves consideration of various
factors unique to these products. Factors such as whether an
animal species expresses relevant receptors or epitopes may affect
species selection (refer to ICH guidance for industry S6
Preclinical Safety Evaluation of Biotechnology-Derived
Pharmaceuticals for more details).
When determining
the MRSD for the first dose of a new therapeutic in humans,
absorption, distribution, and elimination parameters will not be
known for humans. Comparative metabolism data, however, might be
available based on in vitro studies. These data are particularly
relevant when there are marked differences in both the in vivo
metabolite profiles and HEDs in animals. Class experience implies
that previous studies have demonstrated that a particular animal
model is more appropriate for the assessment of safety for a
particular class of therapeutics. For example, in the nonclinical
safety assessment of the phosphorothioate antisense drugs, the
monkey is considered the most appropriate species because monkeys
experience the same dose limiting toxicity as humans (e.g.,
complement activation) whereas rodents do not. For this class of
therapeutics, the MRSD would usually be based on the HED for the
NOAEL in monkeys regardless of whether it was lower than that in
rodents, unless unique dose limiting toxicities were observed with
the new antisense compound in the rodent species.
Once the HED of the NOAEL in the most
appropriate species has been determined, a safety factor should
then be applied to provide a margin of safety for protection of
human subjects receiving the initial clinical dose. This safety
factor allows for variability in extrapolating from animal
toxicity studies to studies in humans resulting from: (1)
uncertainties due to enhanced sensitivity to pharmacologic
activity in humans versus animals; (2) difficulties in detecting
certain toxicities in animals (e.g., headache, myalgias, mental
disturbances); (3) differences in receptor densities or
affinities; (4) unexpected toxicities; and (5) interspecies
differences in ADME of the therapeutic. These differences can be
accommodated by lowering the human starting dose from the HED of
the selected species NOAEL.
In practice, the MRSD for the clinical trial
should be determined by dividing the HED derived from the animal
NOAEL by the safety factor. The default safety factor that should
normally be used is 10. This is a historically accepted value,
but, as described below, should be evaluated based on available
information.
A safety factor of 10 may not be appropriate
for all cases. The safety factor should be raised when there is
reason for increased concern, and lowered when concern is reduced
because of available data that provide added assurance of safety.
This can be visualized as a sliding scale, balancing findings that
mitigate the concern for harm to healthy volunteers with those
that suggest greater concern is warranted. The extent of the
increase or decrease is largely a matter of judgment, using the
available information. It is incumbent on the evaluator to
clearly explain the reasoning behind the applied safety factor
when it differs from the default value of 10, particularly if it
is less than 10.
The following considerations indicate a
safety concern that might warrant increasing the safety factor.
In these circumstances, the MRSD would be calculated by dividing
the HED by a safety factor that is greater than 10. If any of the
following concerns are defined in review of the nonclinical safety
database, an increase in the safety factor may be called for. If
multiple concerns are identified, the safety factor should be
increased accordingly.
- Steep dose response curve. A steep
dose response curve for significant toxicities in the most
appropriate species or in multiple species may indicate a
greater risk to humans.
- Severe toxicities. Qualitatively
severe toxicities or damage to an organ system (e.g., central
nervous system (CNS)) indicate increased risk to humans.
- Nonmonitorable toxicity.
Nonmonitorable toxicities may include histopathologic changes in
animals that are not readily monitored by clinical pathology
markers.
- Toxicities without premonitory signs.
If the onset of significant toxicities is not reliably
associated with premonitory signs in animals, it may be
difficult to know when toxic doses are approached in human
trials.
- Variable bioavailability. Widely
divergent or poor bioavailability in the several animal species,
or poor bioavailability in the test species used to derive the
HED, suggest a greater possibility for underestimating the
toxicity in humans.
- Irreversible toxicity.
Irreversible toxicities in animals suggest the possibility of
permanent injury in human trial participants.
- Unexplained mortality. Mortality
that is not predicted by other parameters raises the level of
concern.
- Large variability in doses or plasma
drug levels eliciting effect. When doses or exposure levels
that produce a toxic effect differ greatly across species or
among individual animals of a species, the ability to predict a
toxic dose in humans is reduced and a greater safety factor may
be needed.
- Nonlinear pharmacokinetics. When
plasma drug levels do not increase in a dose-related manner, the
ability to predict toxicity in humans in relation to dose is
reduced and a greater safety factor may be needed.
- Inadequate dose-response data.
Poor study design (e.g., few dose levels, wide dosing intervals)
or large differences in responses among animals within dosing
groups may make it difficult to characterize the dose-response
curve.
- Novel therapeutic targets.
Therapeutic targets that have not been previously clinically
evaluated may increase the uncertainty of relying on the
nonclinical data to support a safe starting dose in humans.
- Animal models with limited utility.
Some classes of therapeutic biologics may have very limited
interspecies cross-reactivity or pronounced immunogenicity, or
may work by mechanisms that are not known to be conserved
between (nonhuman) animals and humans; in these cases, safety
data from any animal studies may be very limited in scope and
interpretability.
Safety factors of less than 10 may be
appropriate under some conditions. The toxicologic testing in
these cases should be of the highest caliber in both conduct and
design. Most of the time, candidate therapeutics for this
approach would be members of a well-characterized class. Within
the class, the therapeutics should be administered by the same
route, schedule, and duration of administration; should have a
similar metabolic profile and bioavailability; and should have
similar toxicity profiles across all the species tested including
humans. A smaller safety factor might also be used when
toxicities produced by the therapeutic are easily monitored,
reversible, predictable, and exhibit a moderate-to-shallow
dose-response relationship with toxicities that are consistent
across the tested species (both qualitatively and with respect to
appropriately scaled dose and exposure).
A safety factor smaller than 10 could be
justified when the NOAEL was determined based on toxicity studies
of longer duration compared to the proposed clinical schedule in
healthy volunteers. In this case, a greater margin of safety
should be built into the NOAEL, as it was associated with a longer
duration of exposure than that proposed in the clinical setting.
This assumes that toxicities are cumulative, are not associated
with acute peaks in therapeutic concentration (e.g., hypotension),
and did not occur early in the repeat dose study.
Selection of a PAD depends upon many factors
and differs markedly among pharmacological drug classes and
clinical indications; therefore, selection of a PAD is beyond the
scope of this guidance. However, once the MRSD has been
determined, it may be of value to compare it to the PAD derived
from appropriate pharmacodynamic models. If the PAD is from an in
vivo study, an HED can be derived from a PAD estimate by using a
BSA-CF. This HED value should be compared directly to the MRSD.
If this pharmacologic HED is lower than the MRSD, it may be
appropriate to decrease the clinical starting dose for pragmatic
or scientific reasons. Additionally, for certain classes of drugs
or biologics (e.g., vasodilators, anticoagulants, monoclonal
antibodies, or growth factors), toxicity may arise from
exaggerated pharmacologic effects. The PAD in these cases may
be a more sensitive indicator of potential toxicity than the NOAEL
and might therefore warrant lowering the MRSD.
A strategy has been proposed to determine the
maximum recommended starting dose for clinical trials of new
therapeutics in adult healthy volunteers. In summary, usually
NOAELs from the relevant animal studies should be converted to the
HEDs using the standard factors presented in Table 1. Using sound
scientific judgment, a safety factor should be applied to the HED
from the most appropriate species to arrive at the MRSD. This
process is meant to define the upper limit of recommended starting
doses and, in general, lower starting doses can be appropriate.
The process described in this guidance should foster consistency
among sponsors and Agency reviewers.
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EPA, 1992, A Cross-Species Scaling Factor for
Carcinogen Risk Assessment Based on Equivalence of Mg/Kg0.75/Day,
Federal Register, 57:24152-24173.
Freireich, EJ, EA Gehan, DP Rall, LH Schmidt,
and HE Skipper, 1966, Quantitative Comparison of Toxicity of
Anticancer Agents in Mouse, Rat, Hamster, Dog, Monkey, and Man,
Cancer Chemotherapy Reports, 50:219-244.
Geary, RS, JM Leeds, SP Henry, DK Monteith,
and AA Levin, 1997, Antisense Oligonucleotide Inhibitors for the
Treatment of Cancer: 1. QUESTION Pharmacokinetic Properties of
Phosphorothioate Oligodeoxynucleotides, Anti-Cancer Drug Design,
12:383-393.
Lowe, MC and RD Davis, 1998, The Current
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and SK Carter (eds.), Fundamentals of Cancer Chemotherapy, pp.
228-235, New York: McGraw Hill.
Mahmood, I, MD Green, and JE Fisher, 2003,
Selection of the First-Time Dose in Humans: Comparison of
Different Approaches Based on Interspecies Scaling of Clearance,
43(7):692-697.
Mordenti, J, 1986, Man Vs. Beast:
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Reigner, BG and KS Blesch, 2002, Estimating
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Schein, and DP Rall, 1970, The Evaluation of Anticancer Drugs in
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Stahl, WR, 1967, Scaling of Respiratory
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Travis, CC and RK White, 1988, Interspecies
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International Conference on Harmonisation Guidances
ICH guidance for industry S6 Preclinical
Safety Evaluation of Biotechnology-Derived Pharmaceuticals
ICH guidance for industry S3A
Toxicokinetics: The Assessment of Systemic Exposure in Toxicity
Studies
ICH guidance for industry M3 Nonclinical
Safety Studies for the Conduct of Human Clinical Trials for
Pharmaceuticals
b:
Allometric exponent
Body surface area conversion factor (BSA-CF):
A factor that converts a dose (mg/kg) in an animal species to the
equivalent dose in humans (also known as the human equivalent
dose), based on differences in body surface area. A BSA-CF is
the ratio of the body surface areas in the tested species to that
of an average human.
Human equivalent dose (HED): A dose
in humans anticipated to provide the same degree of effect as that
observed in animals at a given dose. In this guidance, as in many
communications from sponsors, the term HED is usually used to
refer to the human equivalent dose of the NOAEL. When reference
is made to the human equivalent of a dose other than the NOAEL
(e.g., the PAD), sponsors should explicitly and prominently note
this usage.
K: A dimensionless factor that
adjusts for differences in the surface area to weight ratio of
species because of their different body shapes.
km: Factor for converting
mg/kg dose to mg/m2 dose
Lowest observed adverse effect level (LOAEL):
The lowest dose tested in an animal species with adverse effects.
Maximum recommended starting dose (MRSD):
The highest dose recommended as the initial dose in a clinical
trial. In clinical trials of adult healthy volunteers, the MRSD
is predicted to cause no adverse reactions. The units of the dose
(e.g., mg/kg or mg/m2) may vary depending on practices
employed in the area being investigated.
Maximum
tolerated dose (MTD): In a toxicity study, the highest dose
that does not produce unacceptable toxicity.
No observed
adverse effect level (NOAEL): The highest dose tested in an
animal species that does not produce a significant increase in
adverse effects in comparison to the control group. Adverse
effects that are biologically significant, even if not
statistically significant, should be considered in determining an
NOAEL.
No observed
effect level (NOEL): The highest dose tested in an animal
species with no detected effects.
Pharmacologically active dose (PAD): The lowest dose tested
in an animal species with the intended pharmacologic activity.
Safety factor
(SF): A number by which the HED is divided to introduce a
margin of safety between the HED and the maximum recommended
starting dose.
W: Body
weight in kg
An analysis was conducted to determine the
effect of the allometric exponent on the conversion of an animal
dose to the HED. One can derive the following equation (see
Appendix C) for converting animal doses to the HED based on body
weights and the allometric exponent (b):
HED = animal NOAEL x (Wanimal/Whuman)(1-b)
Conventionally, for a mg/m2
normalization b would be 0.67, but a number of studies
(including the original Freireich data) have shown that MTDs scale
best across species when b = 0.75. The Interagency
Pharmacokinetics Group has recommended that W0.75 be
used for interspecies extrapolation of doses in carcinogenicity
studies (EPA 1992). There are no data, however, to indicate the
optimal method for converting NOAELs to HEDs. Conversion factors
were calculated over a range of animal and human weights using (Wanimal/Whuman)0.33
or (Wanimal/Whuman)0.25 to assess
the effect on starting dose selection of using b = 0.75 instead of
b = 0.67. The results are shown in Table 2. Using an allometric
exponent of 0.75 had a big effect on the conversion factor for the
smaller species mice and rats. Nonetheless, mice are not commonly
used for toxicology studies to support the first-in-human clinical
trials. In addition, there is evidence that the area under the
plasma concentration versus time curves in rats and humans
correlates reasonably well when doses are normalized to mg/m2
(Contrera et al. 1995). We conclude that the approach of
converting NOAEL doses to an HED based on body surface area
correction factors (i.e., b = 0.67) should be maintained for
selecting starting doses for initial studies in healthy volunteers
since: (1) mg/m2 normalization is widely used
throughout the toxicology and pharmacokinetic research
communities; (2) mg/m2 normalization provides a more
conservative conversion; (3) there are no data to suggest a
superior method for converting NOAELs; and (4) CDER has
significant experience in establishing safe starting doses based
on mg/m2, and it is readily calculated.
Table 2: Effect of
Allometric Exponent on Conversion Factora |
|
|
Conversion Factorsc |
Ratio of 0.75 to 0.67 |
Species |
Weight Rangeb
(kg) |
Standard |
b = 0.67 |
b = 0.75 |
|
Mouse |
0.018-0.033 |
0.081 |
0.075 |
0.141 |
1.88 |
Rat |
0.09-0.40 |
0.162 |
0.156 |
0.245 |
1.57 |
Rabbit |
1.5-3 |
0.324 |
0.33 |
0.43 |
1.30 |
Monkey |
1.5-4 |
0.324 |
0.37 |
0.47 |
1.27 |
Dog |
6.5-13.0 |
0.541 |
0.53 |
0.62 |
1.17 |
a
conversion factor = (Wanimal/Whuman)(1-b)
b
human weight range used was
50-80 kg (110-176 lb)
c
mean conversion factor
calculated across entire animal weight range and human weight
range
The following
summarizes the analysis of the effects of the allometric exponent
on HED calculations:
·
Changing the allometric exponent from 0.67 to 0.75
had a big effect on the conversion factor for the smaller rodent
species; for mice the conversion factors differed by a factor of
almost 2.
·
Converting doses based on an exponent of 0.75 would
lead to higher, more aggressive and potentially more toxic
starting doses.
·
The limited data available suggest that the most
accurate allometric exponent for normalizing MTDs of
antineoplastic agents for interspecies extrapolation is b = 0.75,
but there are no data to indicate the optimal normalization method
for interspecies extrapolation of NOAELs in a broad range of
therapeutic classes. Using mg/m2 is widely adopted
throughout the drug development community.
·
Unless evidence is provided to the contrary, HED
calculations should be based on b = 0.67 (i.e., the
standard conversions based on mg/m2 relationships).
·
There was no notable effect of body weight on
calculation of the HED within the weight ranges examined.
Accurate conversion of a mg/kg dose to a mg/m2
dose depends on the actual weight (and surface area) of the test
species. A popular formula for converting doses is:
(i) mg/m2
= km × mg/kg
where km
= 100/K × W0.33 where K is a value unique to each
species (Freireich et
al. 1966)
or km
= 9.09 × W0.35 where a K value unique to each species
is not needed (Boxenbaum and DiLea 1995; Burtles et al. 1995;
Stahl 1956).
The km value is not truly constant
for any species, but increases within a species as body weight
increases. The increase is not linear, but increases
approximately proportional to W2/3. For example, the km
value in rats varies from 5.2 for a 100 g rat to 7.0 for a 250 g
rat. Strictly speaking, the km value of 6 applies only
to rats at the reference weight of 150 g. For
standardization and practical purposes, a fixed km
factor for each species is preferred. An analysis was undertaken
to determine the effect of different body weights within a species
on the conversion of an animal dose to the HED using km
factors. The km factor was calculated for a range of
body weights using km = 100/K × W0.33. In
Table 3, a working weight range is shown next to the reference
body weight. This is the range within which the HED calculated by
using the standard km value will not vary more than ±20
percent from that which would be calculated using a km
value based on exact animal weight. This is a relativity small
variance considering dose separation generally used in deriving
the NOAEL, in toxicology studies, which are often twofold
separations. For example, suppose a NOAEL in rats is 75 mg/kg and
the average rat weight is 250 g. The km value for a
250 g rat is 7.0.
HED = 75 ´ (7/37) = 14
mg/kg in humans.
Using the standard km value of
6 for rats,
HED = 75
´ (6/37) = 12 mg/kg in
humans.
The HED calculated with the standard km
value of 6 is within 15 percent of the value calculated using the
actual km value of 7. As shown in Table 3, the body
weights producing km factors for which the nominal,
integer conversion factor was within 20 percent of the calculated
factor covered a broad range. This working weight range
encompassed the animal weights expected for the majority of
studies used to support starting doses in humans.
Table 3: Conversion of
Animal Doses to Human Equivalent Doses Based on Body Surface
Area |
Species |
Reference Body Weight
(kg) |
Working Weight Rangea
(kg) |
Body Surface Area (m²) |
To Convert Dose in
mg/kg to Dose in mg/m²
Multiply by km |
To Convert Animal Dose in
mg/kg to HEDb in mg/kg, Either |
Divide
Animal Dose By |
Multiply
Animal Dose By |
Human |
60 |
--- |
1.62 |
37 |
--- |
--- |
Childc |
20 |
--- |
0.80 |
25 |
--- |
--- |
Mouse |
0.020 |
0.011-0.034 |
0.007 |
3 |
12.3 |
0.081 |
Hamster |
0.080 |
0.047-0.157 |
0.016 |
5 |
7.4 |
0.135 |
Rat |
0.150 |
0.080-0.270 |
0.025 |
6 |
6.2 |
0.162 |
Ferret |
0.300 |
0.160-0.540 |
0.043 |
7 |
5.3 |
0.189 |
Guinea
pig |
0.400 |
0.208-0.700 |
0.05 |
8 |
4.6 |
0.216 |
Rabbit |
1.8 |
0.9-3.0 |
0.15 |
12 |
3.1 |
0.324 |
Dog |
10 |
5-17 |
0.50 |
20 |
1.8 |
0.541 |
Primates: |
|
|
|
|
|
|
Monkeysd |
3 |
1.4-4.9 |
0.25 |
12 |
3.1 |
0.324 |
Marmoset |
0.350 |
0.140-0.720 |
0.06 |
6 |
6.2 |
0.162 |
Squirrel monkey |
0.600 |
0.290-0.970 |
0.09 |
7 |
5.3 |
0.189 |
Baboon |
12 |
7-23 |
0.60 |
20 |
1.8 |
0.541 |
Micro-pig |
20 |
10-33 |
0.74 |
27 |
1.4 |
0.730 |
Mini-pig |
40 |
25-64 |
1.14 |
35 |
1.1 |
0.946 |
a
For animal weights within
the specified ranges, the HED for a 60 kg human calculated using
the standard km value will not vary more than
±20 percent from the HED calculated using a km value based on
the exact animal weight.
b
Assumes 60 kg human. For
species not listed or for weights outside the standard ranges,
human equivalent dose can be calculated from the formula: HED =
animal dose in mg/kg x (animal weight in kg/human weight in kg)0.33.
c
The km value is
provided for reference only since healthy children will rarely be
volunteers for phase 1 trials.
d
For example, cynomolgus,
rhesus, and stumptail.
For the typical species used in nonclinical
safety studies, Table 3 also shows the body surface area in m2
for an animal at a particular reference weight. For
example, a 400 g guinea pig has a body surface area of
approximately 0.05 m2. These values come from
published sources with surface area determined experimentally by
various methods. Compilations of this type of data can be found
in published references (Spector 1956).
For animal weights outside the working weight
range in Table 3, or for species not included in the table, an
alternative method is available for calculating the HED. In these
cases the following formula can be used:
HED = Animal dose (mg/kg) × [animal weight
(kg) ÷ human weight (kg)]0.33
For example, assume that a NOAEL of 25 mg/kg
was determined in a study using rabbits weighing 4.0 kg. The 4.0
kg animals are outside the working range for rabbits of 0.9 to 3.0
kg indicated in Table 3.
HED = 25 mg/kg × (4.0 ÷ 60)0.33 =
25 × (0.41) = 10 mg/kg
Alternatively, if the standard conversion
factor was used to calculate the HED
HED = 25 mg/kg ÷ 3.1 = 8.1 mg/kg
The value of 10 mg/kg for the HED is 25
percent greater than the value of 8.1 mg/kg that would be
calculated using the standard conversion factor. For example,
assume that a NOAEL of 25 mg/kg was determined in a study using
rabbits weighing 4.0 kg. The 4.0 kg animals are outside the
working range for rabbits of 0.9 to 3.0 kg indicated in Table 3.
HED = 25 mg/kg × (4.0 ÷ 60)0.33 =
25 × (0.41) = 10 mg/kg
Alternatively, if the standard conversion
factor was used to calculate the HED
HED = 25 mg/kg ÷ 3.1 = 8.1 mg/kg
The value of 10 mg/kg for the HED is 25
percent greater than the value of 8.1 mg/kg that would be
calculated using the standard conversion factor.
The km analysis addresses only
half of the HED conversion process. The range of human sizes
should also be considered to convert the mg/m2 dose
back to an HED dose in mg/kg. To examine the effect of both
animal and human weights on the conversion factor, the principle
of allometry was used. Interspecies biologic parameters are often
related by the power function Y = aWb where W is body
weight and b (allometric exponent) is the slope of the log-log
plot, logy = b × logW + C. Using algebraic manipulation (see
Appendix C), one can derive an equation for converting an animal
dose to the HED based on the body weights of the human and the
animals for a given allometric exponent. For converting an animal
NOAEL in mg/kg to the HED in mg/kg, the equation is:
(ii) HED =
animal NOAEL x (Wanimal/Whuman)(1-b)
Since body surface area is believed to scale
with an allometric exponent (b) of 0.67, one can explore how the
animal and human body weights affect the conversion factor (Wanimal/Whuman)0.33.
The conversion factor was calculated over a
range of animal weights and a range of human weights from 50-80
kg. The results are summarized in Table 4. Column B is the
weight range of the animals used to calculate, in conjunction with
the 50-80 kg range in humans, the conversion factor. The extremes
of the conversion factors for the permutations chosen are shown in
columns C and D. The proposed standard conversion factors are
shown in column E. The percentage difference of these extremes
from the standard is shown in column F. Finally, the range of
animal weights that produced a conversion factor for a 60 kg human
within 20 percent of the standard factor is shown in column G.
The ±10 percent and
±20 percent intervals
across the entire range of weights are graphically illustrated for
rats in Table 5.
Table 4: Effect of Body
Weight on Human Equivalent Dose Conversionsa |
A |
B |
C |
D |
E |
F |
G |
Species |
Animal Weight Rangeb
(kg) |
Conversion Factorc |
% Difference of Extremee
from Standard |
±20%
Rangef for 60 kg Human
(kg) |
sm animal
lg human |
lg animal
sm human |
Standardd |
Mouse |
0.018-0.033 |
0.060 |
0.089 |
0.081 |
-22% |
0.015-0.051 |
Rat |
0.090-0.400 |
0.106 |
0.213 |
0.162 |
-35% |
0.123-0.420 |
Rabbit |
1.5-3.0 |
0.269 |
0.395 |
0.324 |
+22% |
1.0-3.4 |
Monkey |
1.5-4.0 |
0.319 |
0.435 |
0.324 |
+34% |
1.0-3.4 |
Dog |
6.5-13.0 |
0.437 |
0.641 |
0.541 |
-19% |
4.7-16.2 |
a
conversion factor = (Wanimal/Whuman)0.33
b
human weight range used was
50-80 kg (110-176 lb)
c
HED in mg/kg equals animal
dose in mg/kg multiplied by this value
d
See Table 1
e
extreme from column C or D
f
range of animal weights that
produced a calculated conversion factor within 20 percent of the
standard factor (column E) when human weight was set at 60 kg
Table 5: Human and Rat Body
Weights Producing Body Surface Area Dose Conversion Factors Within
10 Percent and 20 Percent of the Standard Factor (0.162)
EFFECT OF BODY WEIGHT ON BSA-CF |
HED =
animal NOAEL∙ (Wanimal/Whuman)exp(1-b),
b = 0.67 for mg/m2 conversion |
Standard conversion to mg/kg = 0.162 |
± 10% |
0.146-0.178 |
|
± 20% |
0.130-0.194 |
|
Rat
Body Weight (kg) |
Human Body Weight (kg)
|
50 |
55 |
60 |
65 |
70 |
75 |
80 |
0.090 |
0.124 |
0.120 |
0.117 |
0.114 |
0.111 |
0.109 |
0.106 |
0.100 |
0.129 |
0.125 |
0.121 |
0.118 |
0.115 |
0.113 |
0.110 |
0.110 |
0.133 |
0.129 |
0.125 |
0.122 |
0.119 |
0.116 |
0.114 |
0.120 |
0.137 |
0.132 |
0.129 |
0.125 |
0.122 |
0.119 |
0.117 |
0.130 |
0.140 |
0.136 |
0.132 |
0.129 |
0.126 |
0.123 |
0.120 |
0.140 |
0.144 |
0.139 |
0.135 |
0.132 |
0.129 |
0.126 |
0.123 |
0.150 |
0.147 |
0.142 |
0.138 |
0.135 |
0.132 |
0.129 |
0.126 |
0.160 |
0.150 |
0.146 |
0.141 |
0.138 |
0.134 |
0.131 |
0.129 |
0.170 |
0.153 |
0.149 |
0.144 |
0.141 |
0.137 |
0.134 |
0.131 |
0.180 |
0.156 |
0.151 |
0.147 |
0.143 |
0.140 |
0.137 |
0.134 |
0.190 |
0.159 |
0.154 |
0.150 |
0.146 |
0.142 |
0.139 |
0.136 |
0.200 |
0.162 |
0.157 |
0.152 |
0.148 |
0.145 |
0.141 |
0.138 |
0.210 |
0.164 |
0.159 |
0.155 |
0.151 |
0.147 |
0.144 |
0.141 |
0.220 |
0.167 |
0.162 |
0.157 |
0.153 |
0.149 |
0.146 |
0.143 |
0.230 |
0.169 |
0.164 |
0.159 |
0.155 |
0.152 |
0.148 |
0.145 |
0.240 |
0.172 |
0.166 |
0.162 |
0.157 |
0.154 |
0.150 |
0.147 |
0.250 |
0.174 |
0.169 |
0.164 |
0.160 |
0.156 |
0.152 |
0.149 |
0.260 |
0.176 |
0.171 |
0.166 |
0.162 |
0.158 |
0.154 |
0.151 |
0.270 |
0.179 |
0.173 |
0.168 |
0.164 |
0.160 |
0.156 |
0.153 |
0.280 |
0.181 |
0.175 |
0.170 |
0.166 |
0.162 |
0.158 |
0.155 |
0.290 |
0.183 |
0.177 |
0.172 |
0.168 |
0.164 |
0.160 |
0.157 |
0.300 |
0.185 |
0.179 |
0.174 |
0.179 |
0.165 |
0.162 |
0.158 |
0.310 |
0.187 |
0.181 |
0.176 |
0.171 |
0.167 |
0.163 |
0.160 |
0.320 |
0.189 |
0.183 |
0.178 |
0.173 |
0.169 |
0.165 |
0.162 |
0.330 |
0.191 |
0.185 |
0.180 |
0.175 |
0.171 |
0.167 |
0.163 |
0.340 |
0.193 |
0.187 |
0.181 |
0.177 |
0.172 |
0.169 |
0.165 |
0.350 |
0.194 |
0.188 |
0.183 |
0.178 |
0.174 |
0.170 |
0.167 |
0.360 |
0.196 |
0.190 |
0.185 |
0.180 |
0.176 |
0.172 |
0.168 |
0.370 |
0.198 |
0.192 |
0.187 |
0.182 |
0.177 |
0.173 |
0.170 |
0.380 |
0.200 |
0.194 |
0.188 |
0.183 |
0.179 |
0.175 |
0.171 |
0.390 |
0.202 |
0.195 |
0.190 |
0.185 |
0.180 |
0.176 |
0.173 |
0.400 |
0.203 |
0.197 |
0.191 |
0.186 |
0.182 |
0.178 |
0.174 |
0.410 |
0.205 |
0.199 |
0.193 |
0.188 |
0.183 |
0.179 |
0.175 |
0.420 |
0.207 |
0.200 |
0.194 |
0.189 |
0.185 |
0.181 |
0.177 |
0.430 |
0.208 |
0.202 |
0.196 |
0.191 |
0.186 |
0.182 |
0.178 |
0.440 |
0.210 |
0.203 |
0.197 |
0.192 |
0.188 |
0.183 |
0.180 |
0.450 |
0.211 |
0.205 |
0.199 |
0.194 |
0.189 |
0.185 |
0.181 |
0.460 |
0.213 |
0.206 |
0.200 |
0.195 |
0.190 |
0.186 |
0.182 |
|
|
|
|
|
|
|
|
|
|
|
The following
are conclusions from these analyses:
·
The ±20
percent interval around the standard conversion factor includes a
broad range of animal and human weights.
·
Given that the human weights will vary broadly, it
is not usually necessary to be concerned about the affect of the
variation of animal weights within a species on the HED
calculation.
·
If an extreme animal weight is encountered in a
toxicology study, one can calculate an accurate conversion factor
using (Wanimal/Whuman)0.33.
Power
equation (mg) = aWb
log(mg) = log(a) + bClog(W)
= bClog(W)
+ c
Given the
weights of animal and human, and animal dose in mg/kg, solve for
HED in mg/kg:
Let H = mg/kg dose in humans
A = mg/kg dose in animals
Wh
= weight of human
Wa
= weight of animal
for animal log(mg) = log(a) + bClog(Wa)
= bClog(Wa)
+ c
replace mg log(ACWa)
= bClog(Wa)
+ c
solve for c c = log(ACWa)
- bClog(Wa)
= log(A) + log(Wa) -
bClog(Wa)
= log(A) + (1-b)log(Wa)
likewise for
human c = log(H) + (1-b)log(Wh)
equate two
equations log(A) + (1-b)log(Wa) = log(H) +
(1-b)log(Wh)
solve for
log(H) log(H) = log(A) + (1-b)log(Wa) -
(1-b)log(Wh)
= log(A) + (1-b)[log(Wa)
- log(Wh)]
= log(A) + log[(Wa/Wh)(1-b)]
log(H) = log[AC(Wa/Wh)(1-b)]
solve for
H H = AC(Wa/Wh)(1-b)
For example, using mg/m2
normalization (b = 0.67) the predicted human MTD in mg/kg based on
a rat LD10 in mg/kg is MTD = LD10
C(Wa/Wh)0.33.
Likewise the HED in mg/kg based on a surface
area conversion given an animal NOAEL is
HED = NOAEL C(Wa/Wh)0.33.
This appendix provides examples of specific
calculations to be taken in deriving an HED based on standardized
factors.
Tables 1 and 3 provide standardized conversion
factors for changing animal or human doses expressed as mg/kg to
doses expressed as mg/m2. Tables 1 and 3 also have
factors (and divisors) for converting animal doses in mg/kg to the
human dose in mg/kg that is equivalent to the animal dose if both
were expressed on a mg/m2 basis. This human dose in
mg/kg is referred to as the HED.
Example 1: Converting to mg/m2
HED
To convert an animal or human dose from mg/kg
to mg/m2, the dose in mg/kg is multiplied by the
conversion factor indicated as km (for mass constant).
The km factor has units of kg/m2; it is equal
to the body weight in kg divided by the surface area in m2.
formula:
mg/kg × km = mg/m2
to convert a dose of 30 mg/kg in a
dog: 30 × 20 = 600 mg/m2
to convert a dose of 2.5 mg/kg in a
human: 2.5 × 37 = 92.5 mg/m2
Example 2: Converting to mg/kg HED in
two steps
To calculate the HED for a particular dose in
animals, one can calculate the animal dose in mg/m2 by
multiplying the dose in mg/kg by the km factor
for that species as described in Example 1. The dose can then be
converted back to mg/kg in humans by dividing the dose
in mg/m2 by the km factor for humans.
formula: (animal mg/kg
dose × animal km) ÷ human km = human mg/kg
dose
to calculate the HED for a 15 mg/kg
dose in dogs:
(15 × 20) ÷ 37 = 300
mg/m² ÷ 37 = 8 mg/kg
Example 3: Converting to mg/kg HED in
one step
The calculation in Example 2 can be simplified
by combining the two steps. The HED can be calculated directly from
the animal dose by dividing the animal dose by the
ratio of the human/animal km factor (third column in
Table 1) or by multiplying by the ratio of the
animal/human km factor (fourth column in Table 1).
Division method
NOAEL
calculation HED
mg/kg ÷ [kmhuman/kmanimal]
15 mg/kg in
dogs 15 mg/kg ÷ 1.8 = 8
mg/kg
50 mg/kg in
rats 50 mg/kg ÷ 6.2 = 8
mg/kg
50
mg/kg in monkeys 50 mg/kg ÷ 3.1 =
16 mg/kg
Multiplication method
NOAEL
calculation
HED
mg/kg × [kmanimal/kmhuman]
15
mg/kg in dogs 15 mg/kg × 0.541 =
8 mg/kg
50
mg/kg in rats 50 mg/kg × 0.162 =
8 mg/kg
50
mg/kg in monkeys 50 mg/kg × 0.324 =
16 mg/kg
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Date created: July 20,2005 |