11264 Federal Register / Vol. 60, No. 40 / Wednesday, March 1, 1995 / Notices

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 § 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 § 10.90(b).

Therefore, this guideline is not being

issued under the authority of § 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.
Federal Register / Vol. 60, No. 40 / Wednesday, March 1, 1995 / Notices 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, doserelated 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-toxiceffect 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.
11266 Federal Register / Vol. 60, No. 40 / Wednesday, March 1, 1995 / Notices

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.
Federal Register / Vol. 60, No. 40 / Wednesday, March 1, 1995 / Notices 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 halflife. 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.
11268 Federal Register / Vol. 60, No. 40 / Wednesday, March 1, 1995 / Notices

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 ‘‘noobserved-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