title: Use of a Target-Mediated Drug Disposition Model to Predict the Human Pharmacokinetics and Target Occupancy of GC1118, an Anti-epidermal Growth Factor Receptor Antibody.
abstract: GC1118 is an anti-epidermal growth factor receptor (EGFR) monoclonal antibody that is currently under clinical development. In this study, the pharmacokinetics (PK) of GC1118 were modelled in monkeys to predict human PK and receptor occupancy (RO) profiles. The serum concentrations of GC1118 and its comparator (cetuximab) were assessed in monkeys with a non-compartmental analysis and a target-mediated drug disposition (TMDD) model after intravenous infusion (3-25 mg/kg) of these drugs. The scaling exponent of the EGFR synthesis rate was determined using a sensitivity analysis. The human cetuximab exposures were simulated by applying different exponents (0.7-1.0) for the EGFR synthesis rate in the allometric monkey PK model. Simulated Cmaxand area under the curve values therein were compared with those previously reported in the literature to find the best exponent for the EGFR synthesis rate in human beings. The TMDD model appropriately described the monkey PK profile, which showed a decrease in clearance (CL; 1.2-0.4 ml/hr/kg) as the dose increased. The exponents for CL (0.75) and volume of distribution (Vd; 1.0) were used for the allometric scaling to predict human PK. The allometric coefficient for the EGFR synthesis rate chosen by the sensitivity analysis was 0.85, and the RO profiles that could not be measured experimentally were estimated based on the predicted concentrations of the total target and the drug-target complex. Our monkey TMDD model successfully predicts human PK and RO profiles of GC1118 and can be used to determine the appropriate dose for a first-in-human study investigating this drug.
authors.affiliation: Department of Clinical Pharmacology and Therapeutics, Seoul St. Mary's Hospital, Seoul, Korea.|PIPET (Pharmacometrics Institute for Practical Education and Training), College of Medicine, The Catholic University of Korea, Seoul, Korea.
authors.forename: Wan-Su
authors.initials: WS
authors.lastname: Park
authors.affiliation: Department of Clinical Pharmacology and Therapeutics, Seoul St. Mary's Hospital, Seoul, Korea.|PIPET (Pharmacometrics Institute for Practical Education and Training), College of Medicine, The Catholic University of Korea, Seoul, Korea.
authors.forename: Seunghoon
authors.initials: S
authors.lastname: Han
authors.affiliation: Department of Clinical Pharmacology and Therapeutics, Seoul St. Mary's Hospital, Seoul, Korea.|PIPET (Pharmacometrics Institute for Practical Education and Training), College of Medicine, The Catholic University of Korea, Seoul, Korea.
authors.forename: Jongtae
authors.initials: J
authors.lastname: Lee
authors.affiliation: Department of Clinical Pharmacology, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Taegon
authors.initials: T
authors.lastname: Hong
authors.affiliation: MOGAM Biotechnology Institute, Yongin, Gyeonggi-do, Korea.
authors.forename: Jonghwa
authors.initials: J
authors.lastname: Won
authors.affiliation: MOGAM Biotechnology Institute, Yongin, Gyeonggi-do, Korea.
authors.forename: Yangmi
authors.initials: Y
authors.lastname: Lim
authors.affiliation: MOGAM Biotechnology Institute, Yongin, Gyeonggi-do, Korea.
authors.forename: Kyuhyun
authors.initials: K
authors.lastname: Lee
authors.affiliation: Green Cross Corp., Yongin, Gyeonggi-do, Korea.
authors.forename: Han Yeul
authors.initials: HY
authors.lastname: Byun
authors.affiliation: Department of Clinical Pharmacology and Therapeutics, Seoul St. Mary's Hospital, Seoul, Korea.|PIPET (Pharmacometrics Institute for Practical Education and Training), College of Medicine, The Catholic University of Korea, Seoul, Korea.
authors.forename: Dong-Seok
authors.initials: DS
authors.lastname: Yim
mesh_terms: D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000097:blood / Q000493:pharmacokinetics*; D000970:Antineoplastic Agents / Q000097:blood / Q000494:pharmacology*; D000068818:Cetuximab / Q000097:blood / Q000494:pharmacology; D003198:Computer Simulation; D004305:Dose-Response Relationship, Drug; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D006801:Humans; D008252:Macaca fascicularis; D008954:Models, Biological
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; C000611922:GC1118; C512478:EGFR protein, human; D066246:ErbB Receptors; D000068818:Cetuximab