Industry Perspective on Current Guidelines, Challenges, and Future Directions for ADME Characterization of Payloads for Antibody‐Drug Conjugates

ABSTRACT A total of 15 antibody‐drug conjugates (ADC)s have been approved by USFDA till December 2025 with the use of nine cytotoxic payload molecules. Small molecule payloads can undergo enzymatic or nonenzymatic biotransformation, distribution, protein or red blood cell binding, transporter mediated disposition and urinary and/or biliary‐fecal excretion. Existing regulatory framework suggests payloads to be characterized for absorption, distribution, metabolism and elimination (ADME) like small molecule therapeutics. Additionally, drug–drug interactions (DDI) relevant investigations are imperative for the payloads. This review focuses on different approaches sponsors have adopted to address payload specific ADME‐DDI questions. The comparison of ADME characteristics of nine approved payloads is presented. It is pointed out that because of lack of ADC specific guidance from regulators, as well as novelty of the ADC platforms, there is no uniformity in addressing ADME properties of payloads, and noticeable differences in approaching the necessity of providing clinical drug interaction data. As ADCs evolve, and more payloads are being developed, the regulatory framework will also need to evolve to guide developers.