title: Physiologically Based Pharmacokinetic Modeling of Therapeutic Proteins.
abstract: Biologics or therapeutic proteins are becoming increasingly important as treatments for disease. The most common class of biologics are monoclonal antibodies (mAbs). Recently, there has been an increase in the use of physiologically based pharmacokinetic (PBPK) modeling in the pharmaceutical industry in drug development. We review PBPK models for therapeutic proteins with an emphasis on mAbs. Due to their size and similarity to endogenous antibodies, there are distinct differences between PBPK models for small molecules and mAbs. The high-level organization of a typical mAb PBPK model consists of a whole-body PBPK model with organ compartments interconnected by both blood and lymph flows. The whole-body PBPK model is coupled with tissue-level submodels used to describe key mechanisms governing mAb disposition including tissue efflux via the lymphatic system, elimination by catabolism, protection from catabolism binding to the neonatal Fc (FcRn) receptor, and nonlinear binding to specific pharmacological targets of interest. The use of PBPK modeling in the development of therapeutic proteins is still in its infancy. Further application of PBPK modeling for therapeutic proteins will help to define its developing role in drug discovery and development.
authors.affiliation: Faculty of Pharmaceutical Sciences, The University of British Columbia, 5505-2405 Wesbrook Mall, Vancouver, British Columbia, Canada V6T 1Z3. Electronic address: harvey.wong@ubc.ca.
authors.forename: Harvey
authors.initials: H
authors.lastname: Wong
authors.affiliation: Faculty of Pharmaceutical Sciences, The University of British Columbia, 5505-2405 Wesbrook Mall, Vancouver, British Columbia, Canada V6T 1Z3.
authors.forename: Timothy W
authors.initials: TW
authors.lastname: Chow
mesh_terms: D000818:Animals; D055808:Drug Discovery / Q000379:methods; D006801:Humans; D008954:Models, Biological; D011506:Proteins / Q000493:pharmacokinetics*; D011961:Receptors, Fc / Q000378:metabolism
chemical_list: D011506:Proteins; D011961:Receptors, Fc
keywords: PBPK; monoclonal antibody; physiologically based pharmacokinetic modelling; therapeutic proteins