Application of pharmacokinetic/pharmacodynamic modeling in the development of antibody-based therapeutics

Mathematical modeling of the time-course of drug exposure (pharmacokinetics, PK) and associated pharmacological effects (pharmacodynamics, PD) has evolved from a simple descriptive endeavor to an essential component of model-based drug development. The role of PK/PD modeling can be more critical for antibody-based therapeutics owing to their complex pharmacological properties. Nonlinear behavior can manifest in most of the physiological processes controlling antibody PK, and mechanisms of drug response are inherently nonlinear and often involve turnover of endogenous ligands and biomarkers. In this chapter, model concepts and features that are common to antibody-based therapeutics are highlighted, along with applications of such models for understanding inter-species differences in concentration-effect relationships, selecting first-in-human doses, designing regimens for clinical studies, and linking PK/PD relationships to clinical outcomes. To improve prospective model predictions of drug efficacy and safety, new approaches will be needed to link antibody disposition with robust systems pharmacology models of drug and disease mechanisms.