Antibody-Drug Conjugates: ADMET Fundamentals, Multi-Analyte Pharmacokinetic Characterization, and Their Role in Clinical Pharmacokinetics and Toxicology

An antibody-drug conjugate (ADC) combines a monoclonal antibody, a chemical linker, and a cytotoxic small-molecule payload into a single therapeutic entity, and this hybrid architecture means an ADC's clinical pharmacokinetic characterization must address not one but at least three distinct, interrelated analytes: the intact conjugate, the total antibody (conjugated plus unconjugated), and the free, released payload (Beck et al., 2017). This article examines the ADMET fundamentals specific to this drug category, the multi-analyte bioanalytical strategy ADC characterization requires, the toxicology considerations arising from the combination of a biologic's disposition pathway with a small molecule's systemic toxicity potential, and the clinical pharmacokinetic study design implications of this layered complexity. The article closes with recommendations for regulatory affairs and clinical pharmacology professionals developing an ADC program.Keywords: antibody-drug conjugate; linker stability; deconjugation; multi-analyte bioanalysis; payload toxicity; target-mediated drug disposition; regulatory artificial intelligence