With a draft FDA guidance on Clinical Pharmacology Considerations for Human Radiolabeled Mass Balance Studies currently under review, there is considerable interest in the design and conduct of human absorption, distribution, metabolism, and excretion (ADME) studies. At the International Society for the Study of Xenobiotics (ISSX) conference in September 2022, Quotient Sciences presented a poster reviewing the approximately 200 radiolabeled studies the organization has performed over the past decade.
The poster included examples where study designs have been adapted to address specific challenges presented by new drug candidates such as:
- Molecules with a long half-life: When the half-life of a drug would make a main residency period too long to be practical, a main residency period of 14–21 days and then several 24-hour return visits can be scheduled to enable the collection of excreta samples for total radioactivity analysis. The recovery curve can then be extrapolated to demonstrate what the likely outcome would have been if a full residency period had been feasible.
- Integrated intravenous microtracer (IVMT)/ADME studies: Integrating an IVMT with a conventional human ADME study is a highly efficient method to assess absolute bioavailability, mass balance, routes and rates of excretion, and metabolite characterization. Extending the overall sample analysis to assess intravenous (IV) mass balance can enable an understanding of key parameters impacting bioavailability, such as fraction absorbed (fa), fraction surviving gut metabolism (fg), and fraction surviving hepatic elimination (fh).
- Potent drugs: Given the challenges of completing the synthesis of the radiolabeled drug at the required specific activity and/or the limitation on the sensitivity of methods and instrumentation for sample analysis, potent drugs often require a hybrid approach to sample analysis, involving both conventional methods and accelerator mass spectrometry (AMS)-enabled methods.
- ADME at steady state: ADME can be investigated at a steady state by administering a single radiolabeled dose after establishing a steady state by multiple dosing of the non-radiolabeled drug. This approach only evaluates the clearance pathway of the radiolabeled drug after a single administration, but it is a practical compromise. An alternative approach is to divide the radiolabeled dose across the multiple doses required to achieve a steady state, but this can result in more challenging analysis requirements.
- Particular study populations: While most human ADME studies can be conducted in healthy male volunteers, occasionally different subject populations may be required (e.g. female subjects, target patient populations, or healthy volunteers with a specific genotype status). Having to identify and recruit patients or provide additional characterization of healthy subjects before they can be recruited adds complexity to the subject recruitment process for the study.
Human ADME study designs should be adapted to address the particular challenges of each molecule under investigation. The approaches described to obtain human ADME data demonstrate the advances in technology available to investigate and understand the disposition of drugs in development.
Iain Shaw, Gareth Whitaker, Katie Stuart