ABSTRACT
During the drug development process, monitoring plasma profiles of parent drug and its metabolites in the nonclinical toxicology studies are required to ensure adequate systemic exposure to characterize organ toxicity and to cover the expected plasma profiles in clinical studies. In some cases, however, significant qualitative or quantitative differences in metabolite profiles occur between the test animal species and humans because of species differences in drug metabolism. Concerns have arisen regarding potential inadequacy of the animal toxicology studies with only parent drugs. In the past few years, the issue of drug metabolites in safety testing and the role of metabolites as potential mediators of the toxicity of new drug products have gained increased attention by both pharmaceutical companies and regulatory agencies [1–4]. After much debate, the Food and Drug Administration (FDA) issued the Guidance for Industry on Safety Testing of Drug Metabolites in February 2008, which outlined recommendations on when and how to characterize and evaluate the safety of “disproportionate” metabolites of small molecule drug products [5]. Metabolites are defined as disproportionate if they present only in humans or present at higher plasma concentrations in humans than in the animals used in nonclinical studies. In cases where a relevant animal species that forms the metabolites at adequate exposure cannot be identified, a bridging study will be required to evaluate safety of the specific metabolite by dosing preformed metabolite(s) in animals. The risk assessment of drug metabolites is considered to be part 606of an investigational new drug (IND) application and recommended to be completed before beginning large-scale clinical trials prior to new drug application (NDA) in the United States.
