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

Area of Science:

• Pharmacokinetics and Drug Metabolism
• Clinical Pharmacology
• Regulatory Science

Background:

• Human radiolabeled mass balance studies are essential for characterizing drug absorption, distribution, metabolism, and excretion (ADME).
• Recent finalized guidance from regulatory bodies like the FDA and NMPA, alongside EMA and PMDA recommendations, underscores the importance of these studies, despite regional differences.
• The IQ Consortium's Human Mass Balance Radiolabeled ADME (hADME) Working Group provides this perspective on critical aspects and advancements in hADME studies.

Purpose of the Study:

• To address key considerations and highlight opportunities for human radiolabeled ADME (hADME) studies.
• To outline current practices and emerging trends in hADME study design.
• To explore the integration of hADME studies with absolute bioavailability (ABA) assessments and their impact on early drug development.

Main Methods:

• Review of current practices and emerging trends in hADME study design.
• Detailed examination of seven clinical designs, including conventional radiolabeled methods and microtracer studies using accelerator mass spectrometry (AMS).
• Exploration of alternative non-radioactive approaches, such as Fluorine-19 nuclear magnetic resonance (¹⁹F-NMR) spectroscopy.

Main Results:

• The review outlines diverse hADME study designs, ranging from traditional radiolabeled approaches to advanced techniques like AMS.
• Alternative non-radioactive methods, including ¹⁹F-NMR, are presented as viable options.
• Integration with absolute bioavailability (ABA) assessments and their impact on early drug development are discussed with case studies.

Conclusions:

• Fit-for-purpose hADME study designs are crucial for comprehensive characterization supporting drug registration.
• These studies provide essential data for regulatory evaluation and product labeling, ultimately benefiting patient well-being.
• The collective effort highlights opportunities to optimize hADME studies in alignment with evolving global regulatory expectations.