論文 - 詳細
| RRC ID | 44551 |
|---|---|
| 著者 | Xiang H, Bender BC, Reyes AE 2nd, Merchant M, Jumbe NL, Romero M, Davancaze T, Nijem I, Mai E, Young J, Peterson A, Damico-Beyer LA. |
| タイトル | Onartuzumab (MetMAb): using nonclinical pharmacokinetic and concentration-effect data to support clinical development. |
| ジャーナル | Clin Cancer Res |
| Abstract |
PURPOSE:We characterized the pharmacokinetics of onartuzumab (MetMAb) in animals and determined a concentration-effect relationship in tumor-bearing mice to enable estimation of clinical pharmacokinetics and target doses. EXPERIMENTAL DESIGN:A tumor growth inhibition model was used to estimate tumoristatic concentrations (TSC) in mice. Human pharmacokinetic parameters were projected from pharmacokinetics in cynomolgus monkeys by the species-invariant time method. Monte Carlo simulations predicted the percentage of patients achieving steady-state trough serum concentrations (Ctrough ss) ≥TSC for every 3-week (Q3W) dosing. RESULTS:Onartuzumab clearance (CL) in the linear dose range was 21.1 and 12.2 mL/d/kg in mice and cynomolgus monkeys with elimination half-life at 6.10 and 3.37 days, respectively. The estimated TSC in KP4 pancreatic xenograft tumor-bearing mice was 15 μg/mL. Projected CL for humans in the linear dose range was 5.74 to 9.36 mL/d/kg with scaling exponents of CL at 0.75 to 0.9. Monte Carlo simulations projected a Q3W dose of 10 to 30 mg/kg to achieve Ctrough ss of 15 μg/mL in 95% or more of patients. CONCLUSIONS:Onartuzumab pharmacokinetics differed from typical bivalent glycosylated monoclonal antibodies with approximately 2-times faster CL in the linear dose range. Despite this higher CL, xenograft efficacy data supported dose flexibility with Q1W to Q3W dose regimens in the clinical setting with a TSC of 15 μg/mL as the Ctrough ss target. The projected human efficacious dose of 10 to 30 mg/kg Q3W should achieve the target TSC of 15 μg/mL. These data show effective pharmacokinetic/pharmacodynamic modeling to project doses to be tested in the clinic. |
| 巻・号 | 19(18) |
| ページ | 5068-78 |
| 公開日 | 2013-9-15 |
| DOI | 10.1158/1078-0432.CCR-13-0260 |
| PII | 1078-0432.CCR-13-0260 |
| PMID | 23894056 |
| MeSH | Animals Antibodies, Monoclonal / administration & dosage* Antibodies, Monoclonal / pharmacokinetics* Blotting, Western Carcinoma, Pancreatic Ductal / drug therapy* Carcinoma, Pancreatic Ductal / metabolism Computer Simulation Dose-Response Relationship, Drug Female Half-Life Humans Immunoenzyme Techniques Immunoprecipitation Macaca fascicularis Mice Mice, Nude Monte Carlo Method Pancreatic Neoplasms / drug therapy* Pancreatic Neoplasms / metabolism Predictive Value of Tests Tissue Distribution Tumor Cells, Cultured Xenograft Model Antitumor Assays |
| IF | 10.107 |
| 引用数 | 17 |
| WOS 分野 | ONCOLOGY |
| リソース情報 | |
| ヒト・動物細胞 | KP4(RCB1005) |