Human Absorption, Metabolism, and Excretion (hAME) Mass Balance Studies in Patients With Cancer

Abstract

Radiolabeled mass balance human studies are a critical component of clinical pharmacology programs supporting the development of new investigational drugs. These studies provide information about absorption, metabolism, and excretion (AME) of the parent drug and metabolite(s) in the human body and are normally conducted in healthy volunteers (HVs). However, in some instances, based on the characteristics and toxicity of the molecule, conducting the study in HVs may not be a viable option and therefore cancer patients (CPs) need to be enrolled. Successful navigation of aspects such as pharmacologic characteristics, dose administration, patient clinical status and comorbidities, confinement period, study extension, team training, and requirements of the hospitals/units are essential to successfully deliver radiolabeled mass balance studies in CPs. This article provides an overview of the main aspects that must be taken into consideration to conduct AME studies in CPs. What is the current knowledge on the topic? Radiolabeled mass balance human studies are an essential study of the clinical pharmacology package needed for the development of new investigational drugs. These studies are normally conducted in HVs. However, in the case of drugs with epigenetic, genotoxic, carcinogenic, or clastogenic effects, and when adverse effects are irreversible and difficult to monitor, or toxicological data from animal models show poor relevance to humans, CPs need to be enrolled. What question did this study address? This article provides an overview of the main aspects that must be taken into consideration to conduct hAME studies in CPs, from protocol design, including patient population, study extension and confinement periods, bioanalytic aspects, and site selection. What does this study add to our knowledge? A thorough evaluation is necessary to decide if a specific hAME study should incorporate CPs or HVs, considering the features of the investigational agent and the specific requirements of the protocol. It will be crucial to have a good knowledge of the ability of the investigational site and pharmacy to manage such complex studies. How might this change clinical pharmacology or translational science? It provided insights into how CPs metabolize drugs, leading to a better understanding of pharmacokinetics and pharmacodynamics aspects of the molecule. Data from these studies can lead to better dosing strategies and reduced toxicity and may help refine predictive models for drug behavior in CPs, improving the translatability of preclinical data. Consequently, the insights obtained can strengthen collaborations among pharmacology, oncology, and toxicology, fostering innovative approaches to drug development.