TY - JOUR T1 - A Model-Based Approach to Predicting the Human Pharmacokinetics of a Monoclonal Antibody Exhibiting Target-Mediated Drug Disposition JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 702 LP - 708 DO - 10.1124/jpet.112.191999 VL - 341 IS - 3 AU - Kenneth T. Luu AU - Simon Bergqvist AU - Enhong Chen AU - Dana Hu-Lowe AU - Eugenia Kraynov Y1 - 2012/06/01 UR - http://jpet.aspetjournals.org/content/341/3/702.abstract N2 - 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 (kon and koff), internalization of the drug-target complex (kint), target degradation rate (kdeg), and target abundance (R0), 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. ER -