research in the pharmaceutical industry although the discussions on how to
conduct metabolite safety testing will continue. Metabolite safety testing is a
very complex subject. It involves metabolite profiling in humans and
toxicology 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 FDA has
suggested that decisions to select metabolites for pharmacological activity
testing, monitoring in humans and animals, and direct safety testing should be
considered on a case-by-case basis.
Regulatory guidances help pharmaceutical scientists design optimal drug
development programs, weigh the risk over benefit ratio in the early phase,
increase assurance of safety, reduce failure and cost in drug development, and
eliminate unnecessary studies. Therefore, pharmaceutical scientists should be
familiar with relevant regulatory guidances in order to assure best practices in
drug development.
Acknowledgment
The authors greatly appreciate Dr. Robert E. Vestal, in critical reading and
editing this chapter.
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232 REGULATORY CONSIDERATIONS OF DRUG METABOLISM AND DRUG