Drug Metabolism in Drug Design and Development Basic Concepts and Practice

format of an NDA is described in 21 CFR 314.50 section. A summary of the
application, technical sections, samples and labeling, and other parts must be
included in the NDA. The technical sections consist of (1) chemistry,
manufacturing, and controls, (2) nonclinical pharmacology and toxicology,
(3) human pharmacokinetics and bioavailability, (4) microbiology, (5) clinical
data, (6) statistical section, and (7) pediatric use. Any studies of the absorption,
distribution, metabolism, and excretion of the drug in animals should be
included in the technical section (2). A summary of analysis of the
pharmacokinetics and metabolism of the active ingredients should be included
in the technical section (3).

7.2.6.4 Common Technical Document for the Registration of Pharmaceuticals
for Human Use (CTD) ICH, 2001) The CTD provides for a harmonized
structure, content, and format for new product applications. The document is
divided into four separate sections. The four sections address the application
organization (M4 organize), the quality section (M4Q), the safety section
(M4S) and the efficacy section (M4E) of the harmonized application. Drug
metabolism and pharmacokinetic data should be summarized in the safety
section that includes the nonclinical overview, nonclinical written summaries,
and nonclinical tabulated summaries. More specifically, in Section 2.6.4.5
metabolism (interspecies comparison) of the written summaries, the following
data should be included:

.Chemical structures and quantities of metabolites in biological samples

.Possible metabolic pathways

.Presystemic metabolism (GI/hepatic first-pass effects)

.in vitrometabolism including P450 studies

.Enzyme induction and inhibition

The CTD also provides templates for the preparation of tabulated
summaries. Similar templates are often used for IND filing by some of
pharmaceutical companies.

7.3 Metabolism Studies Relevant to Metabolite Safety Assessment

7.3.1 Goals and General Strategies

One of major tasks of drug metabolism in drug development is to determine
the exposure of drug metabolites in humans and toxicological species,
especially the assessment of whether human circulating metabolites are present
in the plasma of toxicology species at appropriate levels. The task usually is
accomplished by qualitative and quantitative profiling in human and animal

METABOLISM STUDIES RELEVANT TO METABOLITE SAFETY ASSESSMENT 211