Refinement of the Population Pharmacokinetic Model for the Monoclonal Antibody Matuzumab

摘要: A developed population pharmacokinetic model of the humanized monoclonal antibody (mAb) matuzumab was evaluated by external evaluation. Based on estimates final model, simulations different dosing regimens and covariate effect were performed. The development dataset included 90 patients, evaluation 81 patients; two sets patients from three studies. In all studies, had types advanced carcinoma — mainly colon, rectal pancreatic cancer. They received as multiple 1-hour intravenous infusions in a wide range (development dataset: 400 mg every 3 weeks to 2000 first week followed 1600 weekly; 100 weekly 800 weekly). addition 1256 serum mAb concentrations for development, there 1124 available Serum concentration-time data simultaneously fitted using NONMEM™ software. two-compartment with parameters central volume distribution (V1) peripheral (V2), intercompartmental clearance linear (CLL), an additional nonlinear elimination pathway (Michaelis-Menten constant: concentration half-maximal rate Vmax: maximum rate) relations dataset. Different simulation scenarios performed demonstrate impact incorporated influence strategies profiles. fat-free mass (FFM) V1 CLL. did not support FFM and, after deletion this covariate, refined estimated. showed good precision parameters: relative standard errors (RSEs) <42% ≤51% (excluding higher RSEs correlation between V2 Vmax interindividual variability dataset). robustness ability estimate highly precise combined 171 (RSE <29%). Simulations revealed that profiles minimum steady-state reduced marginal extent proposed dose adaptation. improved new obtained parameter demonstrated robustness. After efficacy results particular could serve tool guide selection ‘targeted’ cancer therapy.