[Federal Register Volume 60, Number 40 (Wednesday, March 1, 1995)]
[Notices]
[Pages 11264-11268]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 95-4957]
[[Page 11263]]
_______________________________________________________________________
Part IX
Department of Health and Human Services
_______________________________________________________________________
Food and Drug Administration
_______________________________________________________________________
International Conference on Harmonisation; Guideline on the Assessment
of Systemic Exposure in Toxicity Studies; Notice
Federal Register / Vol. 60, No. 40 / Wednesday, March 1, 1995 /
Notices
[[Page 11264]]
DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
[Docket No. 94D-0015]
International Conference on Harmonisation; Guideline on the
Assessment of Systemic Exposure in Toxicity Studies; Availability
AGENCY: Food and Drug Administration, HHS.
ACTION: Notice.
-----------------------------------------------------------------------
SUMMARY: The Food and Drug Administration (FDA) is publishing a final
guideline entitled ``Toxicokinetics: Guidance on the Assessment of
Systemic Exposure in Toxicity Studies.'' This guideline was prepared
under the auspices of the International Conference on Harmonisation of
Technical Requirements for Registration of Pharmaceuticals for Human
Use (ICH). The 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: Effective on March 1, 1995. Submit written comments at any time.
ADDRESSES: Submit written comments on the guideline to the Dockets
Management Branch (HFA-305), Food and Drug Administration, rm. 1-23,
12420 Parklawn Dr., Rockville, MD 20857. Copies of the guideline are
available from CDER Executive Secretariat Staff (HFD-8), Center for
Drug Evaluation and Research, Food and Drug Administration, 7500
Standish Pl., Rockville, MD 20855.
FOR FURTHER INFORMATION CONTACT:
Regarding the guideline: Roger L. Williams, Center for Drug
Evaluation and Research (HFD-4), Food and Drug Administration, 5600
Fishers Lane, Rockville, MD 20857, 301-594-6740.
Regarding ICH: Janet J. Showalter, Office of Health Affairs (HFY-
20), 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 international 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 among regulatory
agencies.
ICH was organized to provide an opportunity for tripartite
harmonization initiatives to be developed with input from both
regulatory and industry representatives. FDA also seeks input from
consumer representatives and others. 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; the Centers for Drug
Evaluation and Research and Biologics Evaluation and Research, FDA; and
the Pharmaceutical Research and Manufacturers of America. The ICH
Secretariat, which coordinates the preparation of documentation, is
provided by the International Federation of Pharmaceutical
Manufacturers Association (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.
Harmonization of the assessment of systemic exposure in toxicity
studies was selected as a priority topic during the early stages of the
ICH initiative. In the Federal Register of March 1, 1994 (59 FR 9755),
FDA published a draft tripartite guideline entitled, ``Toxicokinetics:
A Guidance on the Assessment of Systemic Exposure in Toxicity
Studies.'' The notice gave interested persons an opportunity to submit
comments by May 16, 1994.
After consideration of the comments received and revisions to the
guideline, a final draft of the guideline was submitted to the ICH
Steering Committee and endorsed by the three participating regulatory
agencies at the ICH meeting held in October 1994.
The 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.
In the past, guidelines have generally been issued under
Sec. 10.90(b) (21 CFR 10.90(b)), which provides for the use of
guidelines to state procedures or standards of general applicability
that are not legal requirements but are acceptable to FDA. The agency
is now in the process of revising Sec. 10.90(b). Therefore, this
guideline is not being issued under the authority of Sec. 10.90(b), and
it does not create or confer any rights, privileges, or benefits for or
on any person, nor does it operate to bind FDA in any way.
As with all of FDA's guidelines, the public is encouraged to submit
written comments with new data or other new information pertinent to
this guideline. The comments in the docket will be periodically
reviewed, and, where appropriate, the guideline will be amended. The
public will be notified of any such amendments through a notice in the
Federal Register.
Interested persons may, at any time, submit written comments on the
guideline to the Dockets Management Branch (address above). Two copies
of any comments are to be submitted, except that individuals may submit
one copy. Comments are to be identified with the docket number found in
brackets in the heading of this document. The 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 guideline follows:
Toxicokinetics: Guidance on the Assessment of Systemic Exposure in
Toxicity Studies
l. Introduction
This Note for Guidance concerns toxicokinetics only with respect
to the development of pharmaceutical products intended for use in
human subjects.
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. [[Page 11265]]
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 may 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 program may be of value in contributing to the
interpretation of toxicology findings. However, the toxicokinetic
data focus 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 program; 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 feedback 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
judgment 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 decisionmaking 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
toxicokinetics 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 on a toxicity study,
in representative subgroups, in satellite groups (see 3.5 and Note
1) or in separate studies.
Toxicity studies which may be usefully supported by
toxicokinetic information include single and repeated dose toxicity
studies, 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 must also conform to GLP. 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 when they are necessary for the
evaluation of safety.
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 effects or toxicity might also give supporting
evidence of exposure or even replace pharmacokinetic parameters in
some circumstances.
Toxicokinetic monitoring or profiling of 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
nonlinear, dose-related changes in exposure (Note 3) that may have
occurred. Toxicokinetic information may allow better interspecies
comparisons than simple dose/body weight (or surface area)
comparisons.
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 4). 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
The setting of dose levels in 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.
3.4.1 Low dose levels
At the low dose, preferably a no-toxic-effect dose level (Note
5), the exposure in the animals of any toxicity study should ideally
equal or just exceed the maximum expected (or known to be attained)
in patients. It is recognized that this ideal is not always
achievable and that low doses will often need to be determined by
considerations of toxicology; nevertheless, systemic exposure should
be determined.
3.4.2 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.
3.4.3 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 6),
the lowest dose level of the substance producing the maximum
exposure should be accepted as the top dose level to be used (when
no other dose-limiting constraint applies, Note 7).
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 nonlinear kinetics (Note 3). However,
nonlinear 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 dose groups (Note 8) to provide a
basis for risk assessment. [[Page 11266]]
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 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 utilized 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 profile should be considered. For example,
it may be more appropriate for highly protein bound 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/or its relevant metabolite(s) (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 profile, 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
(Note 9).
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 metabolized to one or more
pharmacologically or toxicologically active metabolites which could
make a significant contribution to tissue/organ responses.
When the administered compound is very extensively
metabolized 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 10).
3.9 Statistical evaluation of data
The data should allow a representative assessment of the
exposure. However, because large intra- and inter-individual
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 needed.
Consideration should be given to the calculation of mean or median
values and estimates of variability, but, in some cases, the data of
individual animals may be more important than a refined statistical
analysis of group data.
If data transformation (e.g., logarithmic) is performed, a
rationale should be provided.
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 precision. 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, serum, 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 non-clinical and clinical studies they should
all be suitably validated.
3.11 Reporting
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.
The positioning of the report within the application will depend
upon whether the data are specific to any one toxicity study or is
supportive of all toxicity testing.
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 some individual
animals only, 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, if necessary; appropriate stability data for the
analyte in the matrix sampled would then be required.
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 11) 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 l) at appropriate dose levels at the start and
towards the end of the treatment period of the first repeat dose
study (Note 12). 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,
reduced, or modified for specific compounds where problems have
arisen in the interpretation of earlier toxicity
studies. [[Page 11267]]
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 tissue.
4.5 Carcinogenicity (Oncogenicity) studies1
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.
Particular attention should be paid to the establishment of
appropriate toxicokinetic data when administration is to be in the
diet (Note 13).
Toxicokinetic data may assist in the selection of dose levels in
the light of information about clinical exposure and in the event
that nonlinear kinetics (Note 3) may complicate the interpretation
of the study.
In principle, the ideal study design would ensure 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.
A highest dose based on knowledge of probable systemic exposure
in the test species and in humans may be an acceptable end-point in
testing for carcinogenic potential. Historically, a toxicity end-
point1 has been often used to select the top dose level.
4.5.2 The main studies
The treatment regimen, 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 is conducted in the rat and mouse.
As mentioned in the ``Introduction'' to this section, it is
recommended that reassurance be sought from monitoring that the
exposure in the main study is consistent with profiles of kinetics
established in free-standing or specific dose-ranging studies. Such
monitoring will be appropriate on a few occasions during the study,
but it is not considered essential to continue beyond 6 months.
4.6 Reproductive toxicity studies2
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 animals. At the time of study
evaluation, further information on pharmacokinetics in pregnant or
lactating animals may be required depending on the results obtained.
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 needed for all compounds.
Where adequate systemic exposure might be questioned because of
absence of pharmacological response or toxic effects, toxicokinetic
principles could usefully be applied to determine the exposures
achieved by dosing at different stages of the reproductive process.
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.
Consideration should be given to the possibility that the
kinetics will differ in pregnant and nonpregnant animals.
Toxicokinetics may involve exposure assessment of dams, embryos,
fetuses, or newborn at specified days (Note 14). Secretion in milk
may be assessed to define its role in the exposure of newborns. 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 interpretation of
reproductive toxicity tests in species in which placental transfer
of the substance cannot be demonstrated.
5. Supplementary Notes
Note 1: Definitions of expressions appearing in this ``Note for
Guidance:''
Analyte: The chemical entity assayed in biological samples.
Matrix: Blood, plasma, urine, serum, or other fluid or tissue
selected for assay.
Concomitant toxicokinetics: Toxicokinetic measurements performed
in the toxicity study, either in all animals 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 matrix
level concentration-time curve (AUC) and/or the measurement of
matrix concentrations at the expected peak-concentration time
Cmax, or at some other selected time C(time) are the most
commonly used parameters. Other parameters might be more appropriate
in particular cases.
Monitor: To take a small number of matrix samples (e.g., 1 to 3)
during a dosing interval to estimate C(time) or Cmax.
Profile: To take (e.g., 4 to 8) matrix samples during a dosing
interval to make an estimate of Cmax and/or C(time) and
area under the matrix concentration-time curve (AUC).
Satellite: Groups of animals included in the design and groups:
conduct of a toxicity study, treated and housed under conditions
identical to those of 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 this 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 quantified.
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) concentration.
C(time)-Maximum 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(O-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: Increases in exposure may arise unexpectedly as a result
of nonlinear kinetics 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 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 metabolizing
enzymes. [[Page 11268]]
Note 4: 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 5: 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 6: 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.
Note 7: 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 8: It is often considered unnecessary to assay samples from
control groups. 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 9: 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 metabolites.
Note 10: It is recognised that measurement of metabolite(s) as a
part of toxicokinetic evaluation serves only to assess exposure and
cannot account for possible reactive intermediate metabolites.
Note 11: Treatment regimen encompasses dosage, formulation,
route of administration, and dosing frequency.
Note 12: The first repeat dose study incorporating toxicokinetic
data for each species is normally of 14 day's duration or longer.
Note 13: Additional studies may be required in order to compare
exposure to the compound administered in diet and by gavage or by
routes different from the intended clinical route.
Note 14: 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 in separate studies and expressed as
``placental transfer.''
6. References (other ICH Guidance)
1. Code SlC ``Carcinogenicity: Guidance for Dose Selection Dose
Selection for Carcinogenicity Studies of Therapeutics.''
2. Code S5A ``Detection of Toxicity to Reproduction for
Medicinal Products.''
Dated: February 23, 1995.
William B. Schultz,
Deputy Commissioner for Policy.
[FR Doc. 95-4957 Filed 2-28-95; 8:45 am]
BILLING CODE 4160-01-F