title: Simulation of monoclonal antibody pharmacokinetics in humans using a minimal physiologically based model.
abstract: Compared to small chemical molecules, monoclonal antibodies and Fc-containing derivatives (mAbs) have unique pharmacokinetic behaviour characterised by relatively poor cellular permeability, minimal renal filtration, binding to FcRn, target-mediated drug disposition, and disposition via lymph. A minimal physiologically based pharmacokinetic (PBPK) model to describe the pharmacokinetics of mAbs in humans was developed. Within the model, the body is divided into three physiological compartments; plasma, a single tissue compartment and lymph. The tissue compartment is further sub-divided into vascular, endothelial and interstitial spaces. The model simultaneously describes the levels of endogenous IgG and exogenous mAbs in each compartment and sub-compartment and, in particular, considers the competition of these two species for FcRn binding in the endothelial space. A Monte-Carlo sampling approach is used to simulate the concentrations of endogenous IgG and mAb in a human population. Existing targeted-mediated drug disposition (TMDD) models are coupled with the minimal PBPK model to provide a general platform for simulating the pharmacokinetics of therapeutic antibodies using primarily pre-clinical data inputs. The feasibility of utilising pre-clinical data to parameterise the model and to simulate the pharmacokinetics of adalimumab and an anti-ALK1 antibody (PF-03446962) in a population of individuals was investigated and results were compared to published clinical data.
authors.affiliation: Simcyp Limited, A Certara Company, Blades Enterprise Centre, John Street, Sheffield, S2 4SU, UK, l.li@simcyp.com.
authors.forename: Linzhong
authors.initials: L
authors.lastname: Li
authors.forename: Iain
authors.initials: I
authors.lastname: Gardner
authors.forename: Miroslav
authors.initials: M
authors.lastname: Dostalek
authors.forename: Masoud
authors.initials: M
authors.lastname: Jamei
mesh_terms: D000068879:Adalimumab; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D003198:Computer Simulation; D004333:Drug Administration Routes; D054796:Drug Dosage Calculations; D005240:Feasibility Studies; D006207:Half-Life; D015395:Histocompatibility Antigens Class I / Q000378:metabolism; D006801:Humans; D007074:Immunoglobulin G / Q000378:metabolism; D008196:Lymph / Q000378:metabolism; D008657:Metabolic Clearance Rate; D008954:Models, Biological; D009010:Monte Carlo Method; D010539:Permeability; D011485:Protein Binding; D011961:Receptors, Fc / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D015395:Histocompatibility Antigens Class I; D007074:Immunoglobulin G; D011961:Receptors, Fc; C575087:ascrinvacumab; D000068879:Adalimumab; C100688:Fc receptor, neonatal