Metabolites in Safety Testing

This chapter summarizes the current thinking and practices in the pharmaceutical industry in support of metabolites in safety testing (MIST) related activities. It compares two of several options available for conducting absorption, distribution, metabolism, and excretion (ADME) studies using radiolabled materials. In the first option, radiolabeled studies are not scheduled until after the interpretation of human pharmacokinetics (PK) and metabolism in the first-in-human (FIH) studies, while in the second option, preclinical radiolabeled ADME studies are initiated before the completion of the FIH studies. The chapter discusses some of the liquid chromatography-mass spectrometry (LC-MS) methods available for detecting and characterizing metabolites. Bioanalytical assays, used for detection, characterization and exposure estimation of metabolites, are tiered into (i) metabolite profiling, (ii) standard free quantification/ response factor determination, (iii) qualified assays, and (vi) validated assays