The ‘‘Metabolite in Safety Testing’’ (MIST) document was published by a
committee of the Pharmaceutical Research and Manufactures of America
(PhRMA) in May 2002 (Baillie et al., 2002). It outlines the thinking of the
pharmaceutical industry on how to generate and use metabolite data in
support of drug safety programs, and aimed to promote continued discussions
among industrial scientists and representatives of the regulatory agencies.
Three years later, ‘‘Safety Testing of Drug Metabolites’’ (FDA 2005b,
Table 7.1), a FDA draft guidance was issued. It is the first regulatory
document worldwide to provide recommendations on ‘‘when and how to
identify, characterize, and evaluate the safety of unique human metabolites and
major metabolites of small molecule (nonbiologic) drug products.’’ This
guidance recommends a battery of nonclinical toxicity studies for directly
assessing the safety of a metabolite that is produced only in humans or formed
to a much greater extent in humans than toxicological animal species.
Metabolite safety testing is a very complex subject. It involves quantitative and
qualitative metabolite profiling in humans and animal species with radiolabeled
drugs, pharmacological activity testing of the major metabolites in human
circulation, monitoring of metabolites in selected clinical and nonclinical
studies using a validated bioanalytical assay, and nonclinical toxicity
evaluation of selected metabolites. The entire process requires a great deal of
resources and can take several years. As the FDA guidance indicates, ‘‘the
discovery of unique or major human metabolites late in drug development can
cause development delays and could have possible implications for marketing
approval.’’ On the contrary, decisions to select metabolites for pharmacolo-
gical activity testing, monitoring in humans and animals, and direct safety
testing should be considered on a case-by-case basis. The FDA has
recommended that drug sponsors contact the agency early to discuss such
situations. The MIST document and the FDA draft guidance have opened
another important chapter of drug metabolism research in the pharmaceutical
industry, and the discussions on how to conduct metabolite safety testing will
continue. (Guengerich, 2006; Hastings, 2003; Humphreys and Unger, 2006;
Prueksaritanont, 2006; Smith and Obach, 2005, 2006; Davis-Bruno and
Atrakchi, 2006) In Section 7.3, we discuss basic concepts, general approaches,
and special considerations involved in safety evaluation of metabolites.
7.2.4 Drug–Drug Interaction Studies
The FDA guidance ‘‘Drug Metabolism/Drug Interaction Studies in the Drug
Development Process: Studies in Vitro’’ (FDA, 1997), and the European
Agency for the Evaluation of Medicinal Products (EMEA) guidance ‘‘Note for
Guidance on the Investigation of Drug Interactions’’ were issued in 1997. The
FDA guidance ‘‘in Vivo Drug Metabolism/Drug Interaction Studies’’ was
issued two years later (FDA, 1999). These regulatory documents, for the first
time, clearly define the role and practice of drug metabolism in the drug
development and registration process by stating that ‘‘the metabolism of an
208 REGULATORY CONSIDERATIONS OF DRUG METABOLISM AND DRUG