[Federal Register Volume 59, Number 40 (Tuesday, March 1, 1994)]
[Unknown Section]
[Page 0]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 94-4569]
[[Page Unknown]]
[Federal Register: March 1, 1994]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
[Docket No. 94D-0015]
International Conference on Harmonisation; Draft Guideline on the
Assessment of Systemic Exposure in Toxicity Studies; Availability
AGENCY: Food and Drug Administration, HHS.
ACTION: Notice.
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SUMMARY: The Food and Drug Administration (FDA) is publishing a draft
guideline entitled, ``Toxicokinetics: A Guidance on the Assessment of
Systemic Exposure in Toxicity Studies.'' This guideline was prepared by
the Safety Expert Working Group of the International Conference on
Harmonisation of Technical Requirements for Registration of
Pharmaceuticals for Human Use (ICH). This draft guideline is intended
to help ensure that the assessment of systemic exposure in toxicity
studies to support drug registration is carried out according to sound
scientific principles.
DATES: Written comments by May 16, 1994.
ADDRESSES: Submit written comments on the draft guideline to the
Dockets Management Branch (HFA-305), Food and Drug Administration, rm.
1-23, 12420 Parklawn Dr., Rockville, MD 20857.
FOR FURTHER INFORMATION CONTACT:
Regarding the draft guideline: Alan S. Taylor, Center for Drug
Evaluation and Research (HFD-502), Food and Drug Administration, 5600
Fishers Lane, Rockville, MD 20857, 301-443-2544.
Regarding the ICH: Janet Showalter, Office of Health Affairs (HFY-
50), Food and Drug Administration, 5600 Fishers Lane, Rockville, MD
20857, 301-443-1382.
SUPPLEMENTARY INFORMATION: In recent years, many important initiatives
have been undertaken by regulatory authorities and industry
associations to promote harmonization of regulatory requirements. FDA
has participated in many meetings designed to enhance harmonization and
is committed to seeking scientifically based harmonized technical
procedures for pharmaceutical development. One of the goals of
harmonization is to identify and then reduce differences in technical
requirements for drug development.
ICH was organized to provide an opportunity for tripartite
harmonization initiatives to be developed with technical input from
both regulatory and industry representatives. FDA also seeks input from
consumer representatives and other interested parties. Through notices
such as this, FDA invites public comment on ICH initiatives that have
reached the draft guideline stage. ICH is concerned with harmonization
of technical requirements for the registration of pharmaceutical
products among three regions: the European Union, Japan, and the United
States. The six ICH sponsors are the European Commission, the European
Federation of Pharmaceutical Industry Associations, the Japanese
Ministry of Health and Welfare, the Japanese Pharmaceutical
Manufacturers Association, FDA, and the U.S. Pharmaceutical
Manufacturers Association. The ICH Secretariat, which coordinates the
preparation of documentation, is provided by the International
Federation of Pharmaceutical Manufacturers Associations (IFPMA).
The ICH Steering Committee includes representatives from each of
the ICH sponsors and IFPMA, as well as observers from the World Health
Organization, the Canadian Health Protection Branch, and the European
Free Trade Area.
At a meeting held on October 27 through 29, 1993, the ICH Steering
Committee agreed that the draft tripartite guideline entitled ``The
Assessment of Systemic Exposure in Toxicity Studies'' should be made
available for public comment. The draft guideline will be made
available for comment by the European Commission and Japanese Ministry
of Health and Welfare, as well as by FDA, in accordance with their
respective consultation procedures. After analyzing the comments and
revising the guideline, if appropriate, FDA will determine whether it
will adopt and issue the guideline. The draft guideline discusses
toxicokinetics, which is the generation of pharmacokinetic data in
nonclinical toxicity studies or ancillary studies to assess exposure.
The objectives of toxicokinetics are: (1) To describe the systemic
exposure achieved in animals, its relationship to dose level, and the
time course of the toxicity study; (2) to relate the exposure achieved
in toxicity studies to toxicological findings; (3) to support the
choice of species and treatment regimen in nonclinical toxicity
studies; and (4) to supply information which, along with the toxicity
findings, will contribute to developing additional nonclinical toxicity
studies.
Guidelines are generally issued under Secs. 10.85(d) and 10.90(b)
(21 CFR 10.85(d) and 10.90(b)), which provide for the use of guidelines
to establish procedures or standards of general applicability that are
not legal requirements but that are acceptable to FDA. The agency is
now in the process of considering whether to revise Secs. 10.85(d) and
10.90(b). Therefore, if the agency issues this guideline in final form,
the guideline would not be issued under the authority of Secs. 10.85(d)
and 10.90(b), and would not create or confer any rights, privileges, or
benefits for or on any person, nor would it operate to bind FDA in any
way.
Interested persons may, on or before May 16, 1994, submit written
comments on the draft guideline to the Dockets Management Branch
(address above). Two copies of any comments are to be submitted, except
that individuals may submit single copies. Comments are to be
identified with the docket number found in brackets in the heading of
this document. The draft guideline and received comments may be seen in
the office above between 9 a.m. and 4 p.m., Monday through Friday.
The text of the draft guideline follows:
Toxicokinetics: A Guidance on the Assessment of Systemic Exposure in
Toxicity Studies
1. Introduction
This Note for Guidance concerns toxicokinetics only with respect
to the development of pharmaceutical products intended for use in
human subjects1.
In this context, toxicokinetics is defined as the generation of
pharmacokinetic data, either as an integral component in the conduct
of nonclinical toxicity studies or in specially designed supportive
studies, in order to assess systemic exposure. These data may be
used in the interpretation of toxicology findings and their
relevance to clinical safety issues (see Note 1 for definitions of
other terms used in this document).
The Note for Guidance has been developed in order to provide an
understanding of the meaning and application of toxicokinetics and
to provide guidance on developing test strategies in toxicokinetics.
The guidance highlights the need to integrate pharmacokinetics into
toxicity testing, which should aid in the interpretation of the
toxicology findings and promote rational study design development.
Toxicokinetic measurements are normally integrated within the
toxicity studies and as such are described in this document as
`concomitant toxicokinetics' (Note 1). Alternatively, data may be
generated in other supportive studies conducted by mimicking the
conditions of the toxicity studies.
Toxicokinetic procedures provide a means of obtaining multiple
dose pharmacokinetic data in the test species, if appropriate
parameters are monitored, thus avoiding duplication of such studies;
optimum design in gathering the data will reduce the number of
animals required.
Various components of the total nonclinical pharmacokinetics and
metabolism programme may be of value in contributing to the
interpretation of toxicology findings. However, the toxicokinetic
data focuses on the kinetics of a new therapeutic agent under the
conditions of the toxicity studies themselves.
Toxicokinetics is thus an integral part of the nonclinical
testing programme; it should enhance the value of the toxicological
data generated, both in terms of understanding the toxicity tests
and in comparison with clinical data as part of the assessment of
risk and safety in humans. Due to its integration into toxicity
testing and its bridging character between nonclinical and clinical
studies, the focus is primarily on the interpretation of toxicity
tests and not on characterizing the basic pharmacokinetic parameters
of the substance studied.
As the development of a pharmaceutical product is a dynamic
process which involves continuous feed-back between nonclinical and
clinical studies, no rigid detailed procedures for the application
of toxicokinetics are recommended. It may not be necessary for
toxicokinetic data to be collected in all studies and scientific
judgement should dictate when such data may be useful. The need for
toxicokinetic data and the extent of exposure assessment in
individual toxicity studies should be based on a flexible step-by-
step approach and a case-by-case decision making process to provide
sufficient information for a risk and safety assessment.
2. The Objectives of Toxicokinetics and the Parameters Which May Be
Determined
The primary objective of toxicokinetics is:
to describe the systemic exposure achieved in animals
and its relationship to dose level and the time course of the
toxicity study;
Secondary objectives are:
to relate the exposure achieved in toxicity studies to
toxicological findings and contribute to the assessment of the
relevance of these findings to clinical safety;
to support (Note 1) the choice of species and treatment
regimen in nonclinical toxicity studies;
to provide information which, in conjunction with the
toxicity findings, contributes to the design of subsequent
nonclinical toxicity studies.
These objectives may be achieved by the derivation of one or
more pharmacokinetic parameters (Note 2) from measurements made at
appropriate time points during the course of the individual studies.
These measurements usually consist of plasma (or whole blood or
serum) concentrations for the parent compound and/or metabolite(s)
and should be selected on a case-by-case basis. Plasma (or whole
blood or serum) AUC, Cmax, and C(time) (Note 2) are the most
commonly used parameters in assessing exposure in toxicokinetic
studies. For some compounds it will be more appropriate to calculate
exposure based on the (plasma protein) unbound concentration.
These data may be obtained from all animals in a toxicity study,
in representative subgroups, or in satellite groups (see 3.5 and
Note 3).
Toxicity studies which may be usefully supported by
toxicokinetic information include single and repeated dose toxicity
studies, and reproductive, genotoxicity, and carcinogenicity
studies. Toxicokinetic information may also be of value in assessing
the implications of a proposed change in the clinical route of
administration.
3. General Principles To Be Considered
3.1 Introduction
In the following paragraphs some general principles are set out
which should be taken into consideration in the design of individual
studies.
It should be noted that for those toxicity studies whose
performance is subject to Good Laboratory Practice (GLP) the
concomitant toxicokinetics should also conform to GLP2,3.
Toxicokinetic studies retrospectively designed to generate specific
sets of data under conditions which closely mimic those of the
toxicity studies should also conform to GLP.
3.2 Quantification of exposure
The quantification of systemic exposure provides an assessment
of the burden on the test species and assists in the interpretation
of similarities and differences in toxicity across species, dose
groups, and sexes. The exposure might be represented by plasma
(serum or blood) concentrations or the AUC's of parent compound and/
or metabolite(s). In some circumstances, studies may be designed to
investigate tissue concentrations. When designing the toxicity
studies, the exposure and dose-dependence in humans at therapeutic
dose levels (either expected or established), should be considered
in order to achieve relevant exposure at various dose levels in the
animal toxicity studies. The possibility that there may be species
differences in the pharmacodynamics of the substance (either
qualitative or quantitative) should also be taken into
consideration.
Pharmacodynamic or toxicodynamic effects might also give
supporting evidence of exposure or even replace pharmacokinetic
parameters in some circumstances.
Toxicokinetic monitoring or profiling of the toxicity studies
should establish what level of exposure has been achieved during the
course of the study and may also serve to alert the toxicologist to
non-linear dose related changes in exposure (Note 4) which may have
occurred. Toxicokinetic information may allow better interspecies
comparisons than simple dose/body-weight (or surface area)
comparisons4.
3.3 Justification of time points for sampling
The time points for collecting body fluids in concomitant
toxicokinetic studies should be as frequent as is necessary, but not
so frequent as to interfere with the normal conduct of the study or
to cause undue physiological stress to the animals (Note 5). In each
study, the number of time points should be justified on the basis
that they are adequate to estimate exposure (see 3.2). The
justification should be based on kinetic data gathered from earlier
toxicity studies, from pilot or dose range-finding studies, from
separate studies in the same animal model or in other models
allowing reliable extrapolation.
3.4 Contribution to the setting of dose levels in order to produce
adequate exposure
3.4.1 Introduction
The setting of dose levels in repeat dose toxicity studies is
largely governed by the toxicology findings and the pharmacodynamic
responses of the test species. However, the following toxicokinetic
principles may contribute to the setting of the dose levels.
3.4.2 Low dose levels
At the low dose level, preferably a no-toxic-effect dose level
(Note 6), the exposure in toxicity studies (of all kinds) should
normally exceed that expected or known to be attained in humans at
steady state following therapeutic dose levels. There are, however,
cases where this objective may not be achieved even with the maximum
dose which can be administered.
3.4.3 Intermediate dose levels
Exposure at intermediate dose levels should normally represent
an appropriate multiple (or fraction) of the exposure at lower (or
higher) dose levels dependent upon the objectives of the toxicity
study.
3.4.4 High dose levels
The high dose levels in toxicity studies will normally be
determined by toxicological considerations. However, the exposure
achieved at the dose levels used should be assessed.
Where toxicokinetic data indicate that absorption of a compound
limits exposure to parent compound and/or metabolite(s) (Note 7),
the lowest dose level of the substance producing the maximum
exposure should be accepted as the top dose level to be used
(particularly when no other dose-limiting constraint applies, Note
8).
Very careful attention should be paid to the interpretation of
toxicological findings in toxicity studies (of all kinds) when the
dose levels chosen result in non-linear kinetics (Note 4). However,
non-linear kinetics should not necessarily result in dose
limitations in toxicity studies or invalidate the findings;
toxicokinetics can be very helpful in assessing the relationship
between dose and exposure in this situation.
3.5 Extent of exposure assessment in toxicity studies
In toxicity studies, systemic exposure should be estimated in an
appropriate number of animals and dosed groups (Note 9) to provide a
basis for risk assessment.
Concomitant toxicokinetics may be performed either in all or a
representative proportion of the animals used in the main study or
in special satellite groups (Notes 1, 3 and 5). Normally, samples
for the generation of toxicokinetic data may be collected from main
study animals, where large animals are involved, but satellite
groups may be required for the smaller (rodent) species.
The number of animals to be used should be the minimum
consistent with generating adequate toxicokinetic data. Where both
male and female animals are utilised in the main study it is normal
to estimate exposure in animals of both sexes unless some
justification can be made for not so doing.
Toxicokinetic data are not necessarily required from studies of
different duration if the dosing regimen is essentially unchanged
(see also 4.3).
3.6 Complicating factors in exposure interpretation
Although estimating exposure as described above may aid in the
interpretation of toxicity studies and in the comparison with human
exposure, a few caveats should be noted.
Species differences in protein binding, tissue uptake, receptor
properties, and metabolic profiles should be considered. For
example, it may be more appropriate for some compounds to have
exposure expressed as the free (unbound) concentrations. In
addition, the pharmacological activity of metabolites, the
toxicology of metabolites and antigenicity of biotechnology products
may be complicating factors. Furthermore, it should be noted that
even at relatively low plasma concentrations, high levels of the
administered compound and/or metabolite(s) may occur in specific
organs or tissues.
3.7 Route of administration
The toxicokinetic strategy to be adopted for the use of
alternative routes of administration, for example by inhalation,
topical, or parenteral delivery, should be based on the
pharmacokinetic properties of the substance administered by the
intended route.
It sometimes happens that a proposal is made to adopt a new
clinical route of administration for a pharmaceutical product; for
example, a product initially developed as an oral formulation may
subsequently be developed for intravenous administration. In this
context, it will be necessary to ascertain whether changing the
clinical route will significantly reduce the safety margin.
This process may include a comparison of the systemic exposure
to the compound and its relevant metabolite(s) (plasma AUC and Cmax)
in humans generated by the existing and proposed routes of
administration. If the new route results in increased AUC and/or
Cmax, or a change in metabolic route, the continuing assurance of
safety from animal toxicology and kinetics should be reconsidered.
If exposure is not substantially greater, or different, by the
proposed new route compared to that for the existing route(s) then
additional nonclinical toxicity studies may focus on local toxicity.
3.8 Determination of metabolites
A primary objective of toxicokinetics is to describe the
systemic exposure to the administered compound achieved in the
toxicology species. However, there may be circumstances when
measurement of metabolite concentrations in plasma or other body
fluids is especially important in the conduct of toxicokinetics:
When the administered compound acts as a `pro-drug' and
the delivered metabolite is acknowledged to be the primary active
entity.
When the compound is metabolised to a pharmacologically
or toxicologically active metabolite which would make a significant
contribution to the pharmacological or toxicological response, in
addition to the compound itself (Note 10).
When the administered compound is very extensively
metabolised and the measurement of plasma or tissue concentrations
of a major metabolite is the only practical means of estimating
exposure following administration of the compound in toxicity
studies (Note 11).
3.9 Statistical evaluation of data
The data should allow a representative assessment of the
exposure. However, because large intra- and interindividual
variation of kinetic parameters may occur and small numbers of
animals are involved in generating toxicokinetic data, a high level
of precision in terms of statistics is not normally possible or
required. Consideration should be given to the calculation of mean
or median values and estimates of variability, but in some cases the
data for individual animals may be more important than a refined
statistical analysis of group data.
3.10 Analytical methods
Integration of pharmacokinetics into toxicity testing implies
early development of analytical methods for which the choice of
analytes and matrices should be continually reviewed as information
is gathered on metabolism and species differences.
The analytical methods to be used in toxicokinetic studies
should be specific for the entity to be measured and of an adequate
accuracy and precision6. The limit of quantification should be
adequate for the measurement of the range of concentrations
anticipated to occur in the generation of the toxicokinetic data.
The choice of analyte and the matrix to be assayed (biological
fluids or tissue) should be stated and possible interference by
endogenous components in each type of sample (from each species)
should be investigated. Plasma or whole blood are normally the
matrices of choice for toxicokinetic studies.
If the drug substance is a racemate or some other mixture of
enantiomers, additional justification should be made for the choice
of the analyte [racemate or enantiomer(s)].
The analyte and matrix assayed in nonclinical studies should
ideally be the same as in clinical studies. If different assay
methods are used in nonclinical and clinical studies they should all
be suitably validated6.
3.11 Reporting
A rationale for the toxicokinetic policy adopted should be
reported either in the toxicity study report or in a separate
report. A comprehensive account of the toxicokinetic data generated,
together with an evaluation of the results and of the implications
for the interpretation of the toxicology findings should be given.
An outline of the analytical method should be reported or
referenced. In addition, a rationale for the choice of the matrix
analysed and the analyte measured (see 3.8 and 3.10) should be
given.
4. Toxicokinetics in the Various Areas of Toxicity Testing-Specific
Aspects
4.1 Introduction
Based on the principles of toxicokinetics outlined above, the
following specific considerations refer to individual areas of
toxicity testing. The frequency of exposure monitoring or profiling
may be extended or reduced where necessary.
It may be appropriate to take samples from individual animals on
a study where this may help in the interpretation of the toxicology
findings for these animals.
4.2 Single-dose toxicity studies
These studies are often performed in a very early phase of
development before a bioanalytical method has been developed and
toxicokinetic monitoring of these studies is therefore not normally
possible. Plasma samples may be taken in such studies and stored for
later analysis; appropriate stability data for the analyte in the
matrix sampled would then be needed.
Alternatively, additional toxicokinetic studies may be carried
out after completion of a single dose toxicity study in order to
respond to specific questions which may arise from the study.
Results from single dose kinetic studies may help in the choice
of formulation and in the prediction of rate and duration of
exposure during a dosing interval. This may assist in the selection
of appropriate dose levels for use in later studies.
4.3 Repeated dose toxicity studies
The treatment regimen (Note 12) and species should be selected
whenever possible with regard to pharmacodynamic and pharmacokinetic
principles. This may not be achievable for the very first studies,
at a time when neither animal nor human pharmacokinetic data are
normally available.
Toxicokinetics should be incorporated appropriately into the
design of the studies. It may consist of exposure profiling or
monitoring (Note 1) at appropriate dose levels at the start and
towards the end of the treatment period of the first repeat dose
study (Note 13). The procedure adopted for later studies will depend
on the results from the first study and on any changes in the
proposed treatment regimen. Monitoring or profiling may be extended
or reduced, or modified for specific compounds where problems have
arisen in the interpretation of earlier toxicity studies.
4.4 Genotoxicity studies
For negative results of in vivo genotoxicity studies, it may be
appropriate to have demonstrated systemic exposure in the species
used or to have characterized exposure in the indicator
tissue7.
4.5 Carcinogenicity (Oncogenicity) studies
4.5.1 Sighting or dose-ranging studies
Appropriate monitoring or profiling of these studies should be
undertaken in order to generate toxicokinetic data which may assist
in the design of the main studies (see 4.5.2). Particular attention
should be paid to species and strains which have not been included
in earlier toxicity studies and to the use of routes or methods of
administration which are being used for the first time.
Toxicokinetic data may assist in the selection of dose levels in
the light of information about clinical exposure and in the event
that non-linear kinetics (Note 4) may complicate the interpretation
of the study. Particular attention should be paid to the
establishment of appropriate toxicokinetic data when administration
is to be in the diet (Note 14).
It is recommended that dose levels in oncogenicity studies
generate a range of systemic exposure values that exceed the maximum
therapeutic exposure for humans by varying multiples. However, it is
recognized that this idealized selection of dose levels may be
confounded by unavoidable species-specific problems. Thus, the
emphasis of this guidance is on the need to estimate systemic
exposure, to parent compound and/or metabolite(s) at appropriate
dose levels and at various stages of an oncogenicity study, so that
the findings of the study may be considered in the perspective of
comparative exposure for the animal model and humans.
In practice, the `Maximum Tolerated Dose' (MTD) has been used,
whenever possible, as the top dose level in these studies. However,
it has been suggested8 that it may be acceptable to select a
high dose level based on consideration of the kinetics in humans and
in the test species.
For nongenotoxic compounds of comparatively low general
toxicity, in addition to a toxicity-based endpoint (MTD) which
remains acceptable, it has been proposed9 reasonable to define
a level of animal exposure that would be considered sufficiently
great, compared to human exposure, to provide reassurance of an
adequate test of carcinogenicity. It is considered important to
compare exposure rather than administered dose because the latter
does not take into account inter-species differences in
pharmacokinetics9.
4.5.2 The main studies
The treatment regimen and species and strain selection should,
as far as is feasible, be determined with regard to the available
pharmacokinetic and toxicokinetic information. In practice, the vast
majority of these studies are conducted in the rat and mouse.
Reassurance should be sought from the toxicokinetic data that the
exposure level in the chosen species is consistent with the results
from the dose ranging studies.
Concomitant toxicokinetics may be confined to monitoring
exposure at appropriate dose levels at a number of stages in the
study. Appropriate stages may be early in the study, and after
prolonged treatment, for example at one year. It is not considered
necessary to monitor exposure beyond one year in these studies. The
design for each test should be selected on a compound by compound
basis utilizing data gathered from earlier studies (see 4.5.1).
4.6 Reproductive toxicity studies
4.6.1 Introduction
It is preferable to have some information on pharmacokinetics
before initiating reproduction studies, since this may suggest the
need to adjust the choice of species, study design, and dosing
schedules. At this time, the information need not be sophisticated
or derived from pregnant or lactating animals10. At the time of
study evaluation, further information on pharmacokinetics in
pregnant or lactating animals may be necessary depending on the
results obtained10.
The limitation of exposure in reproductive toxicity is usually
governed by maternal toxicity. Thus, while toxicokinetic monitoring
in reproductive toxicity studies may be valuable in some instances,
especially with compounds with low toxicity, such data are not
generally necessary for all compounds.
Where appropriate, toxicokinetic principles should be applied to
determine the exposures achieved in the different stages of the
reproduction toxicity studies. A satellite group of female animals
may be used to collect the toxicokinetic data.
4.6.2 Fertility studies
The general principles for repeated dose toxicity studies apply
(see 4.3). The need to monitor these studies will depend on the
dosing regimen used and the information already available from
earlier studies in the selected species.
4.6.3 Studies in pregnant and lactating animals
The treatment regimen during the exposure period should be
selected on the basis of the toxicological findings and on
pharmacokinetic and toxicokinetic principles.
Toxicokinetics may involve exposure assessment of dams, embryos,
fetuses, or newborn at specified days (Note 15). Secretion in milk
may be assessed to define its role in the exposure of newborn. In
some situations, additional studies may be necessary or appropriate
in order to study embryo/fetal transfer and secretion in milk.
Consideration should be given to the possibility that
pharmacokinetics may differ in pregnant and non-pregnant animals.
Consideration should be given to the interpretation of
reproductive toxicity tests in species in which placental transfer
of the substance cannot be demonstrated (Note 16).
5. Supplementary Notes
Note 1 Definitions of expressions appearing in this ``Note for
Guidance'':
Analyte: the chemical entity assayed in biological samples.
Concomitant toxicokinetics: toxicokinetic measurements performed
in the toxicity study animals, either in all or in representative
subgroups or in satellite groups.
Exposure: exposure is represented by pharmacokinetic parameters
demonstrating the local and systemic burden on the test species with
the test compound and/or its metabolites. The area under the plasma
level concentration-time curve (AUC) and/or the measurement of
plasma concentrations at the expected peak-concentration time Cmax,
or at some other selected time C(time), are the most commonly
used parameters. Others might be more appropriate in particular
cases.
Monitor: to take a small number of blood samples (say 1-3)
during a dosing interval to estimate C(time) or Cmax.
Profile: to take (say) 4-8 blood samples during a dosing
interval to make an estimate of Cmax and/or C(time) and area
under the plasma concentration-time curve (AUC).
Satellite groups: groups of animals included in the design and
conduct of the toxicity study and housed with the main-study
animals, but used primarily for toxicokinetics.
Support: in the context of a toxicity study - to ratify or
confirm the design of a toxicity study with respect to
pharmacokinetic and metabolic principles. This process may include
two separate steps:
a) confirmation using toxicokinetic principles that the animals
on a study were exposed to appropriate systemic levels of the
administered compound (see 3.4) and/or its metabolite(s).
b) confirmation that the metabolic profile in the species used
was acceptable; data to support b) will normally be derived from
metabolism studies in animals and in humans.
Validate: in the context of an analytical method - to establish
the accuracy, precision, reproducibility, response function and the
specificity of the analytical method with reference to the
biological matrix to be examined and the analyte to be
quantified6.
Note 2 Symbols and definitions according to ``Manual of Symbols,
Equations and Definitions in Pharmacokinetics'', Committee for
Pharmacokinetic Nomenclature of the American College of Clinical
Pharmacology, Philadelphia, PA, May 1982:
Cmax - Maximum (peak) plasma concentration
C(time) - Plasma concentration at a specified time after
administration of a given dose
tmax - Time to reach peak or maximum concentration following
administration
AUC(0-t) - Area under concentration-time curve from zero to
time t. It should be noted that AUC(0-infinity) is a special
case of AUC(0-t).
Other measurements, for example urinary excretion, may be more
appropriate for some compounds. Other derived parameters, for
example bioavailability, half-life, fraction of unbound drug, and
volume of distribution may be of value in interpreting toxicokinetic
data. Thus, the selection of parameters and time points has to be
made on a case-by-case basis considering the general principles as
outlined in Section 3.
Note 3 Satellite groups (Note 1) to toxicity studies should be
housed in conditions identical to those provided for the main test
animals and be subject to the same dosing procedures and animal
husbandry procedures.
Note 4 Increases in exposure may arise unexpectedly as a result
of non-linear kinetics11 due to saturation of a clearance
process. Increasing exposure may also occur during the course of a
study for those compounds which have a particularly long plasma
half-life. Careful attention should also be paid to compounds which
achieve high plasma Cmax values over comparatively short time
periods within the dosing interval. Conversely, unexpectedly low
exposure may occur during a study as a result of auto-induction of
metabolic enzymes.
Note 5 If samples are taken from main study animals it should be
considered whether samples should be taken from all the dosed
animals and the controls in order to treat all animals on the study
in the same way, or whether samples should be taken from
representative subgroups of the same size.
Note 6 In this context, a `no-toxic-effect dose level' (deemed
to be the same as `no-observed-adverse-effect dose level') is
defined as a dose level at which some pharmacological response may
be observed, but at which no adverse effect is found.
Note 7 In these circumstances it should be established that
absorption is the rate limiting step and that limitations in
exposure to the administered substance are not due to an increased
clearance by metabolism.
Note 8 The limits placed on acceptable volumes which can be
administered orally to animals may constrain the dose levels
achievable for comparatively non-toxic compounds administered as
solutions or suspensions.
Note 9 It is often considered unnecessary to assay samples from
control groups, but samples may be collected and then assayed if it
is deemed that this may help in the interpretation of the toxicity
findings, or in the validation of the assay method.
Note 10 Measurement of metabolite concentrations may be
especially important when documentation of exposure to human
metabolite(s) is needed in the nonclinical toxicity studies in order
to demonstrate adequate toxicity testing of these metabolites5.
Note 11 It is recognized that measurement of metabolite(s) as a
part of toxicokinetic evaluation serves only to assess exposure and
cannot account for possible reactive intermediate
metabolites12.
Note 12 Treatment regimen encompasses dosage, formulation, route
of administration, and dosing frequency.
Note 13 The first repeat dose study incorporating toxicokinetic
data for each species is normally of 14 days' duration or longer.
Note 14 Additional studies may be necessary in order to compare
exposure to the compound administered in diet and by gavage or by
routes different from the intended clinical route.
Note 15 Separate pharmacokinetic studies may be needed in order
to establish the pharmacokinetic profile in species and strains
selected for reproductive toxicity studies which have not been
previously selected for general toxicity studies. It should be noted
that while it is important to consider the transfer of substances
entering the embryo-fetal compartment, fetal exposure is the
parameter which is most often assessed in practice and expressed as
`placental transfer'.
Note 16 For practical reasons, it is normally accepted that
placental transfer has not been demonstrated if the concentration in
the whole fetus does not exceed 1% of the maternal plasma
concentration.
7. References
1 Design of Toxicokinetic Studies, Smith D. A., Humphrey M. J.,
and Charuel, Xenobiotica, 1990, Vol. 20, No. 11. 1187-1199.
2 Food and Drug Administration, Department of Health and Human
Services, Statement dated June 9th 1993.
3 Commission of the European Communities, Statement on
Applicability of Good Laboratory Practice (III/3824/92).
4 Opportunities for Integration of Pharmacokinetics,
Pharmacodynamics, and Toxicokinetics in Rational Drug Development,
Peck C. C. et al., Pharmaceutical Research, 1992, Vol. 9, No. 6,
826-833.
5 Proceedings of The First International Conference on
Harmonisation, Brussels 1991. Ed: D'Arcy, P. F. and Harron, D. W. G.
(1992), page 188.
6 Analytical methods validation: Bioavailability, Bioequivalence
and Pharmacokinetic Studies, Shah, V. P. et al., European Journal of
Drug Metabolism and Pharmacokinetics, 1991, Vol. 16, No. 4, 249-255.
7 ICH Joint Position Paper: Genotoxicity, 1993.
8 Proceedings of The First International Conference on
Harmonisation, Brussels 1991. Ed: D'Arcy, P. F. and Harron, D. W. G.
(1992), pages 185 and 331.
9 ICH Position Paper: `High Dose Selection for Carcinogenicity
Studies', 1993.
10 ICH Tripartite Guideline: `Guideline on Detection of Toxicity
to Reproduction for Medicinal Products', 1993.
11 Gibaldi M. and Perrier D., `Pharmacokinetics' Second Edition,
Chapter 7, Marcel Dekker Inc., New York (1982).
12 What is an appropriate measure of exposure when testing drugs
for carcinogenicity in rodents? Monro, A., Toxicology and Applied
Pharmacology, 1992, 112, 171-181.
Dated: February 23, 1994.
Michael R. Taylor,
Deputy Commissioner for Policy.
[FR Doc. 94-4569 Filed 2-24-94; 1:35 pm]
BILLING CODE 4160-01-F
