A MIST conception: what has been learned from twenty years of human metabolite safety assessment?

In this review, we trace origins of the joint initiative of the pharmaceutical industry and major regulatory authorities to provide a framework for the identification, quantification, and testing of drug metabolites (i.e., Metabolites in Safety Testing; MIST). Dr. Tom Baillie was hugely instrumental in initiating and guiding this process and continues to be influential in this area up to present day. Current industry approaches to MIST are described, including evolution in techniques for metabolite identification, measurement, and characterization, plus a survey of contemporary technologies used to assess whether human metabolites are disproportionate and thus may require standalone safety assessment, clinical pharmacology, and PK/PD studies. The multiple steps involved with nonclinical safety assessment of metabolites formed in humans to a greater extent than animals are covered, which leads to frequently unnecessary safety assessment of stable circulating human metabolites. Two recent case studies of marketed drugs are included, where it is shown that additional nonclinical safety assessment of disproportionate human metabolite(s) did not appear to provide useful information relevant to human safety. This retrospective also addresses impact of MIST guidance on overall drug safety, including relative contributions of on- vs. off-target activity of parent drug vs. reactive human metabolites leading to idiosyncratic toxicity for a series drugs withdrawn from the US market since 1980. The special case of metabolite involvement in developmental and reproductive toxicity profile is described. The manuscript concludes with discussion of how MIST guidelines over the last 20 years have likely impacted on industry productivity for new molecular entities.