Satoshi Yoshiba1, Mendel Jansen2, Nobuko Matsushima3, Shuquan Chen4, Jeanne Mendell5. 1. Translational Medicine and Clinical Pharmacology, Daiichi Sankyo Co., Ltd, 1-2-58, Hiromachi, Shinagawa, Tokyo, 140-8710, Japan. yoshiba.satoshi.s8@daiichisankyo.co.jp. 2. Translational Medicine and Clinical Pharmacology, Daiichi Sankyo Development, Ltd, Gerrards Cross, UK. 3. Translational Medicine and Clinical Pharmacology, Daiichi Sankyo Co., Ltd, 1-2-58, Hiromachi, Shinagawa, Tokyo, 140-8710, Japan. 4. Biostatistics and Data Management, Daiichi Sankyo Pharma Development, Edison, NJ, USA. 5. Translational Medicine and Clinical Pharmacology, Daiichi Sankyo Pharma Development, Edison, NJ, USA.
Abstract
PURPOSE: The purpose of this analysis was to develop a population pharmacokinetic (PK) model for patritumab, a fully human monoclonal antibody that targets human epidermal growth factor receptor 3. METHODS: A total of 833 serum concentrations were included in this analysis; serum concentrations were obtained from 145 subjects (136 with non-small cell lung cancer, nine with solid tumors) treated with patritumab [9 or 18 mg/kg intravenously every 3 weeks (q3w)] in one phase 1 and one phase 1b/2 study. Data were analyzed by nonlinear mixed-effect modeling. RESULTS: Patritumab PKs were best described through a two-compartment model with first-order elimination and interindividual variability on clearance (CL), volume of the central compartment (V c), distributional clearance, and volume of the peripheral compartment. In the final model, CL and V c were estimated as 0.0238 L/h and 3.62 L, respectively. Body weight (BW) and baseline albumin were found to be covariates for CL and BW was a covariate for V c. Covariates associated with hepatic and renal impairment were not significant on CL. Simulations showed that BW-based dosing reduced interindividual variability in patritumab exposure compared with fixed dosing. CONCLUSIONS: The PK of patritumab was linear at the doses studied and well described by the two-compartment model. Hepatic and renal impairment did not appear to affect PK. Our results support BW-based dosing of patritumab on a q3w schedule.
PURPOSE: The purpose of this analysis was to develop a population pharmacokinetic (PK) model for patritumab, a fully human monoclonal antibody that targets humanepidermal growth factor receptor 3. METHODS: A total of 833 serum concentrations were included in this analysis; serum concentrations were obtained from 145 subjects (136 with non-small cell lung cancer, nine with solid tumors) treated with patritumab [9 or 18 mg/kg intravenously every 3 weeks (q3w)] in one phase 1 and one phase 1b/2 study. Data were analyzed by nonlinear mixed-effect modeling. RESULTS:Patritumab PKs were best described through a two-compartment model with first-order elimination and interindividual variability on clearance (CL), volume of the central compartment (V c), distributional clearance, and volume of the peripheral compartment. In the final model, CL and V c were estimated as 0.0238 L/h and 3.62 L, respectively. Body weight (BW) and baseline albumin were found to be covariates for CL and BW was a covariate for V c. Covariates associated with hepatic and renal impairment were not significant on CL. Simulations showed that BW-based dosing reduced interindividual variability in patritumab exposure compared with fixed dosing. CONCLUSIONS: The PK of patritumab was linear at the doses studied and well described by the two-compartment model. Hepatic and renal impairment did not appear to affect PK. Our results support BW-based dosing of patritumab on a q3w schedule.
Entities:
Keywords:
Modeling; Non-small cell lung cancer; Patritumab; Population pharmacokinetics