Monoclonal Antibody Therapeutics: ADMET Fundamentals, Target-Mediated Drug Disposition, and Their Role in Clinical Pharmacokinetics and Toxicology

Monoclonal antibody therapeutics behave pharmacokinetically unlike almost any small-molecule drug, following disposition pathways governed by the neonatal Fc receptor recycling system and, frequently, by target-mediated drug disposition (TMDD) rather than conventional hepatic or renal clearance mechanisms (Dostalek et al., 2013). This article examines the ADMET fundamentals specific to this drug category, the assays used to characterize monoclonal antibody disposition, the distinctive nonlinear pharmacokinetic behavior TMDD produces, species selection considerations for nonclinical toxicology given the requirement for pharmacologic relevance, and the clinical pharmacokinetic and dosing strategy implications that follow from these properties. The article also addresses internal-versus-outsourcing considerations specific to large-molecule bioanalytical and toxicology support, and closes with recommendations for regulatory affairs and clinical pharmacology professionals developing a monoclonal antibody program.Keywords: monoclonal antibody; target-mediated drug disposition; FcRn; nonlinear pharmacokinetics; immunogenicity; bioanalytical method; regulatory artificial intelligence