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Death receptor 5 agonistic antibody PRO95780: preclinical pharmacokinetics and concentration-effect relationship support clinical dose and regimen selection.
Cancer Chemother Pharmacol. 2013 Jun 16;
Authors: Xiang H, Reyes AE, Eppler S, Kelley S, Damico-Beyer LA
Abstract
PURPOSE: PRO95780, a human monoclonal antibody (mAb) against death receptor 5 (DR5/TRAIL-R2/TNFRSF10B), was developed for the treatment for cancer. Our objective was to characterize pharmacokinetics (PK) in mice, rats, and cynomolgus monkeys and concentration-effect relationships of PRO95780 in xenograft mouse models of human cancers; this would guide the selection of dose and regimen for clinical trials. METHODS: The PK profiles were determined in mice, rats, and cynomolgus monkeys. Three xenograft models with a wide range of in vitro sensitivities to PRO95780 were selected for efficacy studies. Tumoristatic serum concentrations (TSCs) were determined using PK/pharmacodynamic (PD) modeling with tumor growth as a PD endpoint. A species-invariant time PK scaling method was employed to estimate disposition in humans using PK data in cynomolgus monkeys. Furthermore, the predicted human PK parameters were used to estimate dose and regimen to achieve TSC observed in mice at the steady-state trough concentrations (C trough ss) in the clinic. RESULTS: Linear PK was observed across species. A serum concentration of 22�?g/mL was identified to be the target TSC in mice. A dose of 10�mg/kg administered once every 2�weeks (Q2W) was predicted to achieve a TSC at C trough ss in 95�% of patients. CONCLUSIONS: PRO95780 has linear PK in mice, rats, and monkeys. Estimated TSCs varied among different xenograft models. A projected target dose in humans is achievable for Q2W administration within the dose range used for other commercial mAbs.
PMID: 23771513 [PubMed - as supplied by publisher]
Caspase-8 inhibitor selleck chemical Caspase-9 inhibitor CASPASE INHIBITOR selleck chemical
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