title: A model-based approach to predicting the human pharmacokinetics of a monoclonal antibody exhibiting target-mediated drug disposition.
abstract: In the drug discovery and development setting, the ability to accurately predict the human pharmacokinetics (PK) of a candidate compound from preclinical data is critical for informing the effective design of the first-in-human trial. PK prediction is especially challenging for monoclonal antibodies exhibiting nonlinear PK attributed to target-mediated drug disposition (TMDD). Here, we present a model-based method for predicting the PK of PF-03446962, an IgG2 antibody directed against human ALK1 (activin receptor-like kinase 1) receptor. Systems parameters as determined experimentally or obtained from the literature, such as binding affinity (k(on) and k(off)), internalization of the drug-target complex (k(int)), target degradation rate (k(deg)), and target abundance (R(0)), were directly integrated into the modeling and prediction. NONMEM 7 was used to model monkey PK data and simulate human PK profiles based on the construct of a TMDD model using a population-based approach. As validated by actual patient data from a phase I study, the human PK of PF-03446962 were predicted within 1- to 2-fold of observations. Whereas traditional approaches fail, this approach successfully predicted the human PK of a monoclonal antibody exhibiting nonlinearity because of TMDD.
authors.affiliation: Clinical Pharmacology-Oncology Business Unit, Pfizer Global Research and Development, La Jolla, California, USA. kenneth.luu@pfizer.com
authors.forename: Kenneth T
authors.initials: KT
authors.lastname: Luu
authors.forename: Simon
authors.initials: S
authors.lastname: Bergqvist
authors.forename: Enhong
authors.initials: E
authors.lastname: Chen
authors.forename: Dana
authors.initials: D
authors.lastname: Hu-Lowe
authors.forename: Eugenia
authors.initials: E
authors.lastname: Kraynov
mesh_terms: D030201:Activin Receptors, Type I / Q000276:immunology; D000818:Animals; D000911:Antibodies, Monoclonal / Q000493:pharmacokinetics*; D061067:Antibodies, Monoclonal, Humanized; D017321:Clinical Trials, Phase I as Topic; D003198:Computer Simulation; D004305:Dose-Response Relationship, Drug; D016503:Drug Delivery Systems; D004353:Drug Evaluation, Preclinical; D004730:Endothelium, Vascular / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D000882:Haplorhini; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology; D051379:Mice; D008954:Models, Biological; D020349:Surface Plasmon Resonance; D014471:Umbilical Veins
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D007074:Immunoglobulin G; C575087:ascrinvacumab; D030201:Activin Receptors, Type I