Design, conduct, and interpretation of human mass balance studies and strategies for assessing metabolites-in-safety testing (MIST) in drug development

The human mass balance study is one of the most informative and critical studies in the clinical pharmacology programs that is needed for understanding of the absorption, metabolism, and excretion (AME) of a new chemical entity. In this chapter, the design, conduct and interpretation of the human mass balance (or human AME) study is presented, and recommendations on how to address common issues are reviewed. Micro-radioactive dosing as an alternative to traditional radiometric designs for mass balance and metabolite profiling is discussed. In addition, analytical strategies for assessment of human metabolites-in safety testing (MIST) are reviewed and new approaches to the determination of coverage of human drug metabolites in preclinical species are discussed. Novel approaches toward understanding AME and absolute bioavailability (ABA), leveraging the latest bioanalytical techniques, is proposed.