bioanalysis in preclinical and clinical studies and for safety evaluation
in vitro and in toxicological animal species. To avoid delays in the drug
development process due to the discovery of unique human metabolites
in the late stages of clinical trials, some pharmaceutical companies have
moved radiolabeled human ADME studies to early stages of clinical
trials.
Regulatory guidances not only direct trends in drug metabolism research in
the pharmaceutical industry but also provide detailed recommendations on
experimental design, study execution, and data interpretation. For example,
the newly published FDA draft guidance on DDI (FDA, 2006a) includes
specific CYP probe substrates, inhibitors and inducers forin vitroandin vivo
drug interaction studies. To provide high quality and complete drug
metabolism data for drug development and registration, it is essential to
follow regulatory guidances when designing, conducting, and reporting drug
metabolism studies.
The FDA, the Ministry of Health & Welfare in Japan, and the European
Medicinal Evaluation Agency (EMEA) in Europe are three major regional
regulatory agencies. Each of the agencies publishes their own regulatory
guidelines. In addition, to achieve greater harmonization in the interpretation
and application of regulatory guidelines for drug product registration and to
reduce or obviate the need to duplicate the testing carried out during the
research and development of new medicines, the International Conference on
Harmonization of Technical Requirements for Registration of Pharma-
ceuticals for Human Use (ICH) publishes guidances. EMEA publishes and
distributes the Step 2 ICH guidelines for comments and endorses the Step 4
guidelines (http://www.emea.eu.int). The FDA publishes a notice with the full
text of the Step 2 or Step 4 ICH guidances in the Federal Register. Step 4
guidances are available for use on the date they are published in the Federal
Register (CDER: http://www.fda.gov/cder/guidance/index.htm)..) In this chap-
ter, we briefly review the FDA and the ICH guidances relevant to drug
metabolism. In particular, from the regulatory perspective, the overall
strategies, study designs, data interpretation, and special considerations in
the assessment of metabolite safety and drug–drug interaction potential are
discussed.
7.2 Regulatory Guidances Relevant to Drug Metabolism
Table 7.1 lists selected ICH and the FDA guidances that are associated with
drug metabolism, such as the guidances on drug interaction (FDA, 1999, 1997,
2006a) and safety testing of metabolites (FDA, 2005b); or focus on other
subjects with more limited relevance to drug metabolism, such as guidances on
toxicokinetics (ICH, 1995a) and regulatory submissions (FDA, 1995, 2003a).
In the following sections, we attempt to give a brief description of these
regulatory guidances.
204 REGULATORY CONSIDERATIONS OF DRUG METABOLISM AND DRUG