Authors: Amrita V Kamath Dan Lu Priyanka Gupta Denise Jin Yan Xin Ann Brady JeanPhilippe Stephan Hao Li Janet Tien Jing Qing Lisa A DamicoBeyer
Publish Date: 2011/12/28
Volume: 69, Issue: 4, Pages: 1071-1078
Abstract
MFGR1877A is a human IgG1 monoclonal antibody that binds to fibroblast growth factor receptor 3 FGFR3 and is being investigated as a potential therapy for relapsed/refractory FGFR3+ multiple myeloma The purpose of these studies was to characterize the pharmacokinetics PK of MFGR1877A in mouse rat and monkey and predict its human PK and efficacious dosePK of MFGR1877A was determined in athymic nude mice Sprague–Dawley rats and cynomolgus monkeys after administration of single intravenous doses Human PK profiles were projected from monkey PK profiles using a speciesinvariant time method and human population PK parameters were estimated using a nonlinear twocompartment model comprising specific targetmediated and nonspecific clearance pathways The antitumor efficacy in mice bearing human tumor xenografts was used in conjunction with inhibitory activity in cell proliferation assays and human PK projections to estimate clinical efficacious doseThe PK of MFGR1877A in mice was nonlinear in the dose range of 1–50 mg/kg while in rats and monkeys PK was nonlinear in the dose range of 1–10 mg/kg and linear at doses ≥10 mg/kg The predicted nonspecific clearance range in humans was 26–44 mL/day/kg Doses ranging from 2 to 3 mg/kg weekly to 6–10 mg/kg every 4 weeks were predicted to achieve the target exposure in ≥90 of multiple myeloma patients
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