Early Assessment of Exposure of Drug Metabolites in Humans Using Mass Spectrometry

Abstract

Safety of marketed drugs has been and continues to be the major focus of regulatory authorities around the world. Recent regulatory guidance on metabolites in safety testing (MIST) recommends that the exposure of human circulating metabolites at steady state (SS) should be equal to or higher in at least one of the preclinical species used in safety assessment. The measurement of SS plasma concentrations of drug metabolites is complex, resource intensive, and time consuming. Various analytical approaches based on MS, UV, NMR, and radioactivity responses have been reported to assess the metabolite exposure margin between toxicology species and humans. Therefore, it is important to understand the utility and limitations of analytical instruments to apply an appropriate analytical tool to address specific questions posed at different stages of drug development. This article describes the analytical techniques to assess the metabolite exposure margin between toxicology species and humans.