Onartuzumab (MetMAb): Using Nonclinical Pharmacokinetic and Concentration–Effect Data to Support Clinical Development
| Autor: | Hong Xiang, Mally Romero, Lisa A. Damico-Beyer, Judy Young, Mark Merchant, Elaine Mai, Amy C. Peterson, Ihsan Nijem, Nelson L. Jumbe, Brendan C. Bender, Arthur E. Reyes, Teresa Davancaze |
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| Rok vydání: | 2013 |
| Předmět: |
Cancer Research
Blotting Western Mice Nude Pharmacology Immunoenzyme Techniques Mice Pharmacokinetics Predictive Value of Tests Tumor Cells Cultured Animals Humans Immunoprecipitation Computer Simulation Tissue Distribution Dosing Dose-Response Relationship Drug Chemistry Antibodies Monoclonal Half-life Serum concentration Xenograft Model Antitumor Assays Pancreatic Neoplasms Macaca fascicularis Dose–response relationship Oncology Onartuzumab Pharmacodynamics Tumor growth inhibition Female Monte Carlo Method Carcinoma Pancreatic Ductal Half-Life |
| Zdroj: | Clinical Cancer Research. 19:5068-5078 |
| ISSN: | 1557-3265 1078-0432 |
| DOI: | 10.1158/1078-0432.ccr-13-0260 |
| Popis: | 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. Clin Cancer Res; 19(18); 5068–78. ©2013 AACR. |
| Databáze: | OpenAIRE |
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