Applications of Pharmacometrics in Antibody–Drug Conjugate Development

Antibody-drug conjugates (ADCs), which integrate a cytotoxic drug known as the payload into a tumor-targeting monoclonal antibody via a linker, have emerged as promising candidates for cancer therapy and are a new avenue for targeted cancer therapy. The pharmacokinetic (PK) profiles of ADCs are distinctive due to their unique distribution, catabolism, and elimination. Their deconjugation in circulation and variations in the drug-to-antibody ratio increase the complexity of their PK profiles. Pharmacometric models depicting the PK properties and exposure-response (E-R) relationships of ADCs are important for optimizing dosing regimens and supporting decisions during ADC development. This review considers the PK profiles of ADCs, physiologically based PK models, semi-mechanistic and mechanistic PK models, population PK models, and E-R analyses for dose optimization. The prospects and challenges for ADCs, especially the urgent need for advanced analytical technology and modeling approaches, are also outlined.