Mechanistic PBPK Modeling of Antibody–Drug Conjugates: Integration of Antibody Disposition, Linker Deconjugation, and Payload Pharmacokinetics

Antibody–drug conjugates (ADCs) represent a rapidly advancing class of biological drugs used for cancer treatment. The integration of monoclonal antibodies, connected via chemical linkers, ensures the targeting potential of small-molecule payloads with cytotoxic potency. The United States Food and Drug Administration (USFDA) has announced its plan to phase out in vivo tests for monoclonal antibodies and other drugs with replacement from New Approach methodologies (NAMs) data. NAMs can include in vitro (cell-line and organoid testing), in silico modeling or other innovative approaches that have the capacity to predict the toxicity of compounds including ADCs. Among these proposed NAMs, physiologically based pharmacokinetic (PBPK) modeling has the capacity to provide a mechanistic framework capable of integrating antibody disposition, linker deconjugation dynamics, and payload small-molecule pharmacokinetics (PK). This review provides details about ADC and the developing ADC PBPK model, covering the tissue architecture, two-pore vascular transport, model hierarchy from minimal to whole-body model, parameterization strategies, regulatory scenario, applications, limitations and their future prospects.