Human radiolabeled mass balance studies: objectives, utilities and limitations.

The determination of metabolic pathways of a drug candidate through the identification of circulating and excreted metabolites is vitally important to understanding its physical and biological effects. Knowledge of metabolite profiles of a drug candidate in animals and humans is essential to ensure that animal species used in toxicological evaluations of new drug candidates are appropriate models of humans. The recent FDA final guidance recommends that human oxidative metabolites whose exposure exceeds 10% of the parent AUC at steady-state should be assessed in at least one of the preclinical animal species used in toxicological assessment. Additional toxicological testing on metabolites that have higher exposure in humans than in preclinical species may be required. The metabolite profiles in laboratory animals and humans are generally accomplished by mass balance and excretion studies in which radiolabeled drugs are administered to these species. The biological fluids are collected, analysed for total radioactivity and evaluated for a quantitative profile of metabolites. Thus, these studies not only determine the rates and routes of excretion but also provide very critical information on the metabolic pathways of drugs in preclinical species and humans. In addition, these studies are required by regulatory agencies for the new drug approval process. Despite the usefulness of these radiolabeled mass balance studies, there is little concrete guidance on how to perform or assess these complex studies. This article examines the objectives, utilities and limitations of these studies and how these studies could be used for the determination of the metabolite exposure in animals and humans.