Pharmacokinetic modeling frameworks for complex antibody-drug conjugates analytes: clinical pharmacology...

Antibody-drug conjugates (ADCs) present unique pharmacokinetic (PK) challenges due to analyte heterogeneity, dynamic drug-to-antibody ratio (DAR) distributions, target-mediated disposition, and systemic release of cytotoxic payloads. Unlike monoclonal antibodies or small molecules alone, ADCs require integrated modeling approaches capable of simultaneously describing total antibody, conjugated species, DAR-specific subpopulations, and free drug exposure. Over the past decade, pharmacometric strategies have evolved from empirical population PK models toward semi-mechanistic and system-based frameworks incorporating deconjugation kinetics, intracellular processing, and target-mediated drug disposition. In this review, we examine current PK modeling paradigms for ADCs, evaluate their strengths and limitations in clinical development, and discuss how quantitative frameworks inform dose selection, exposure-response relationships, and translational prediction. As ADC platforms diversify, rigorous mechanistic PK modeling is increasingly central to optimizing therapeutic index and regulatory decision-making.