Challenges and solutions to metabolites in safety testing: impact of the International Conference on Harmonization M3(R2) guidance.

IMPORTANCE OF THE FIELD: The FDA and the International Conference on Harmonization (ICH) recently issued regulatory guidance on metabolites in safety testing (MIST). One of the key differences between these two types of guidance is the threshold for a major metabolite: > 10% of AUC of the parent drug at steady-state (the FDA) versus > 10% of drug-related exposure (ICH). The FDA agreed to adopt the ICH M3 threshold in 2010. Both guidance require metabolite profiling in humans during early clinical development which have presented significant challenges from two aspects: i) how to balance the recommendation of front-loading of metabolism studies with the need to invest resources appropriately according to the stage of drug development and ii) how to fully utilize alternative bioanalytical approaches to generate reliable data for enabling prompt and informed decisions, without always resorting to resource-intensive good laboratory practices bioanalysis. AREAS COVERED IN THIS REVIEW: This review summarizes current thinking in the pharmaceutical industry on these two aspects. WHAT THE READER WILL GAIN: this review aims to provide the reader with a clear understanding of the importance and timing of various metabolism studies and an overview of the latest bioanalytical approaches of quantitation of metabolites in the absence of reference standards. TAKE HOME MESSAGE: the approaches outlined are not intended to be universal solutions to MIST. The researcher still has to consider a case-by-case approach with scientific justification to comply with the MIST guidance.