An industry perspective on tiered approach to the investigation of metabolites in drug development

Abstract

Background: A tiered approach to drug metabolite measurement and identification is often used industry wide to fulfill regulatory requirements specified in recent US FDA and European Medicines Agency guidance. Although this strategy is structured in its intent it can be customized to address unique challenges which may arise during early and late drug development activities. These unconventional methods can be applied at any stage to facilitate metabolite characterization. Results: Two case studies are described NVS 1 and 2. NVS 1: plasma concentrations, measured using a radiolabeled MS-response factor exploratory method, were comparable to those from a validated bioanalytical method. The NVS 2 example showed how in vitro analysis helped to characterize an unexpectedly abundant circulating plasma metabolite M3. Conclusion: A tiered approach incorporating many aspects of conventional and flexible analytical methodologies can be pulled together to address regulatory questions surrounding drug metabolite characterization.