Characterization of drug-drug interaction for antibody-drug conjugates and risk assessment using various approaches including physiologically based pharmacokinetic modeling

Abstract

ADCs represent a rapidly growing class of cancer therapeutics and hold significant promise. As of December 2025, fourteen ADCs have received FDA approval, with more than 100 additional ADCs currently in clinical development. Assessment of ADC DDI risk requires consideration of both mAb and cytotoxic payload components of ADCs. The mAb-related DDIs may occur under certain circumstances typically as a pharmacodynamic target mediated interaction, but no clinically meaningful impact has been reported. Whereas, the payload, once released from the ADC, is expected to behave as a small molecule and may pose an enzyme- or transporter-mediated DDI risk. Although the risk of payloads as precipitant of DDI is low and likely of little if any clinical relevance, the potential of circulating payloads as a DDI object still exists depending on its disposition pathways and pharmacokinetic characteristics. In this manuscript, fifteen approved ADCs with eight distinct payloads—MMAE, MMAF, DXd, ozogamicin, DM1, DM4, SN-38, and PBD SG3199 were reviewed for its DDI characterization and risk assessment. Different approaches, including in vitro and in vivo characterization, especially the use of PBPK modeling, were summarized. Insight from the Pharm industry on ADC DDI risk assessment as well as regulatory impact and future directions were discussed.