Drug Metabolism in Drug Design and Development Basic Concepts and Practice

7.2.1 Toxicokinetic Studies

The ICH published a guidance for toxicokinetics in 1995 entitled ‘‘the
Assessment of Systemic Exposure in Toxicity Studies’’ (ICH, S3A, Table 7.1)
(ICH, 1995a). In order to aid in the interpretation of toxicology findings and
promote rational study design development, this document gives guidance on
developing testing strategies in toxicokinetics and the need to integrate
pharmacokinetics into toxicity testing. The primary objective of toxicokinetics
is to evaluate systemic exposure achieved in animals and its relationship to dose
levels in toxicity studies (Cayen, 1995a, 1995b). Assessment of the systemic
exposure in toxicokinetic studies is mainly carried out by measurement of drug
concentrations in plasma or other body fluids using a validated bioanalytical
assay. However, in some cases, measurement of metabolite concentrations in
plasma or excreta is important in the conduct of toxicokinetics when (1) a
metabolite is the primary active entity of a prodrug, (2) a metabolite is
pharmacologically or toxicologically active and makes a significant contribu-
tion to tissue/organ responses, and (3) the measurement of a metabolite in
plasma or tissues is the only practical means of estimating exposure of drug-
related components because the parent drug is very extensively metabolized.
The decision to monitor a circulating metabolite by a validated bioanalytical
assay in toxicity studies often relies on metabolite profiles of a radiolabeled
drug in the toxicology species as well as knowledge of pharmacological activity
or toxicity of the metabolite.

TABLE 7.1 (Continued)

Regulatory guidance ICH FDA

Regulatory
submission
format and
contents

M4––Common technical

document

for the registration of

pharmaceuticals

for human use

IND meetings for human

drugs and biologics (FDA, 2001b)

Content and format of

investigational new drug

applications (INDs) for phase I

studies of drugs (FDA, 1995)

CFR Title 21, Part

312––Investigational

new drug application

(FDA, 2003a)

CFR Title 21, 314––Applications

for FDA approval to

market a new drug (FDA, 2003b)

Labeling for human

prescription drug and

biological products

implementing the

new content and format

requirements (FDA, 2006b)

206 REGULATORY CONSIDERATIONS OF DRUG METABOLISM AND DRUG