Drug Metabolism in Drug Design and Development Basic Concepts and Practice

of this book specifically addresses regulatory guidelines for drug metabolism
studies.
In addition to the CTD, metabolism-related data are also incorporated into
the various sections of the product label to provide prescribing physicians with
the relevant information to either recommend adjusting the dose or avoid
prescribing the medicine when patients are taking concomitant interacting
medications. These are discussed in more detail in the later half of the chapter
(Section 9.7).

9.2 STAGING AND TYPES OF DRUG METABOLISM STUDIES

IN DRUG DEVELOPMENT

Drug metabolism studies are conducted throughout the discovery and
development lifetime of a drug. The type of metabolism studies performed
depends on the stage of the drug development process (Fig. 9.1). As mentioned
before, the focus of the drug metabolism studies in early drug discovery is to
aid in selection and identify potential liabilities, whereas, studies conducted
after the compound is selected for development are for registrational filing and
to provide information for the product label. The timing of the metabolism-
related studies depends on how the information generated will be used in the
compound’s development. Since the focus of this chapter is on the role of
metabolism studies after the compound is selected to be taken into clinical

IND 1 stin Man NDAApproval

ADME in humans

Species comparison

in vitro-in vivo correlation

Soft-spot and reactive

metabolite analysis

Candidate

Rapid screen for

CYP inhibition and

induction, reaction

phenotyping

Clinical development

Preclinical

Lead development Phase I Phase II Phase III

selection

Discovery

Optimization

Definitive CYP inhibition

and induction studies

Definitive reaction

phenotyping studies

Tissue distribution and

ADME in animals with

radiolabeled material

Optimization

FIGURE 9.1 Staging of metabolism-related studies in the drug discovery and
development process. The timing and the sequence of the studies presented here are
based on author’s experience in conducting these studies in Bristol Myers Squibb. The
studies mentioned here include the core set of metabolism-related work that is currently
conducted for registrational filing.

STAGING AND TYPES OF DRUG METABOLISM STUDIES 265