Application of pharmacokinetics-pharmacodynamics/clinical response modeling and simulation for biologics drug development

Biologics, specifically monoclonal antibody (mAb) drugs, have unique pharmacokinetic (PK) and pharmacodynamic (PD) characteristics as opposed to small molecules. Under the paradigm of model-based drug development, PKPD/clinical response models offer critical insight in guiding biologics development at various stages. On the basis of the molecular structure and corresponding properties of biologics, typical mechanism-based [target-mediated drug disposition (TMDD)], physiologically based PK, PKPD, and doseresponse meta-analysis models are summarized. Examples of using TMDD, PKPD, and meta-analysis in helping starting dose determination in first-in-human studies and dosing regimen optimization in phase II/III trials are discussed. Instead of covering the entirety of model-based biologics development, this review focuses on the guiding principles and the core mathematical descriptions underlying the PK or PKPD models most used. (c) 2012 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 101:43674382, 2012