development, there are no common approaches and systems one can use to
address these issues. The approaches used depend on the nature of the issue.
For example, if it is a toxicology finding in long-term toxicity studies in animals
then having an understanding about the quantitative and qualitative
differences in metabolism across species, along with exposure to drug and
drug-derived metabolites, helps to further define the issue and assists in the
planning of key follow-up metabolism-related studies. There are three examples
at the end of this chapter that illustrate the role of metabolism-related studies to
address issues in the drug development process. These three examples and
numerous examples in the literature further highlight the need for a thorough
understanding of thein vitroandin vivometabolism profile of a drug.
9.1.3 Drug Metabolism and Regulatory Requirements
Ultimately, the metabolism-related data that is generated during the drug
development process is to satisfy the regulatory agencies requirements.
Table 9.1 shows the table of contents for the drug metabolism sections in the
common technical document (CTD) for a drug application. Table 9.2 shows
the template used to summarize drug metabolism data for anin vivostudy that
is included in the summary tables of the CTD. There are a number of
regulatory guidelines published by the FDA and EMEA regarding the type of
in vitroandin vivometabolism data needed for registration of a drug. Chapter 7
TABLE 9.1 The sections of the CTD where metabolism studies are
summarized.
2.6.4 Pharmacokinetics written summary
The sequence of the pharmacokinetics written summary:
Brief summary
Methods of analysis
Absorption
Distribution
Metabolism
Excretion
Pharmacokinetic drug interactions
Other pharmacokinetic studie
Discussion and conclusions2.6.4.5 Metabolism (interspecies comparison)
The following data should be summarized in this section:
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 inhibitionINTRODUCTION TO THE ROLE OF DRUG METABOLISM 263