Integrated strategies for assessment of metabolite exposure in humans during drug development: analytical challenges and clinical development considerations.

ABSTRACT

Monitoring the exposure of a drug and its metabolites in humans and preclinical species during drug development is required to ensure that the safety of drug-related components in humans are adequately assessed in the standard toxicology studies. Recently published FDA guidance on metabolites in safety testing (MIST) has generated broad discussion from various perspectives. Most of the opinions and experiences shared among the scientific community are scientifically sound and practical. There are various approaches to assess the metabolite exposure margin between toxicology species and humans either by direct or indirect comparison or by qualitative or quantitative comparison. The choice of when and how to pursuit metabolite assessment is based on the overall development strategy of the compound. Therefore, it is important to understand the utility and limitations of analytical instruments in order to apply an appropriate analytical tool to address specific questions posed at different stages of drug development. The urgency of metabolite monitoring depends on the intrinsic nature of the compound, therapeutic intent and objective of the clinical development. The strategy for assessing metabolite exposure in humans should be a holistic approach considering clinical situations and cumulative knowledge of the metabolism of the drug in order to appropriately address metabolite safety in humans. A one-size-fits-all approach is rarely the best use of resources.