Advances in Human Mass Balance Studies: An IQ Consortium Perspective on Current Practices and Emerging Trends

Human radiolabeled mass balance studies are crucial for comprehensively characterizing the absorption, distribution, metabolism, and excretion (ADME) of investigational drugs, providing essential data for drug development, regulatory evaluation, and product labeling. The IQ Consortium's Human Mass Balance Radiolabeled ADME (hADME) Working Group developed this perspective to address key considerations and highlight opportunities for these studies. This is particularly relevant as regulatory guidance, such as the 2024 US Food and Drug Administration (FDA) and China's National Medical Products Administration (NMPA), have finalized dedicated guidance documents, along with recommendations from other global regulatory bodies (including European Medicines Agency (EMA) and Pharmaceuticals and Medical Devices Agency (of Japan; PMDA)); still, there are some regional differences. This review outlines current practices and emerging trends in hADME study design. It details seven clinical designs, from conventional radiolabeled approaches to microtracer studies that employ analytical techniques, such as accelerator mass spectrometry (AMS). It further highlights alternative non-radioactive approaches, including the use of Fluorine-19 nuclear magnetic resonance (¹⁹F-NMR) spectroscopy. The manuscript also explores the integration of hADME studies with absolute bioavailability (ABA) assessments and highlights their impact on early drug development with case studies. This collective effort by the IQ working group highlights fit-for-purpose study designs to ensure comprehensive ADME characterization supporting drug registration and patient well-being.