Evaluation of the toxicology and pharmacokinetics of recombinant factor VIII Fc fusion protein in animals
| Autor: | Kenneth S. Loveday, Jennifer A. Dumont, David R. Light, Haiyan Jiang, Glenn F. Pierce |
|---|---|
| Rok vydání: | 2015 |
| Předmět: |
Male
No-observed-adverse-effect level Fc fusion Recombinant Fusion Proteins Cmax Pharmacology Hemophilia A Rats Sprague-Dawley Toxicology Neonatal Fc receptor Species Specificity Von Willebrand factor Pharmacokinetics hemophilia medicine Animals Humans rFVIIIFc Volume of distribution Prothrombin time Factor VIII biology medicine.diagnostic_test Chemistry Thrombosis Hematology Recombinant Proteins Immunoglobulin Fc Fragments Rats Macaca fascicularis HEK293 Cells Area Under Curve biology.protein Female Biological half-life toxicology |
| Zdroj: | Thrombosis Research. 136:1266-1272 |
| ISSN: | 0049-3848 |
| DOI: | 10.1016/j.thromres.2015.07.019 |
| Popis: | Introduction Recombinant factor VIII Fc fusion protein (rFVIIIFc) is a novel recombinant factor VIII with a prolonged half-life, developed for the treatment of hemophilia A. Studies that evaluated the toxicological effects of rFVIIIFc in 2 pharmacologically relevant species, cynomolgus monkeys and Sprague Dawley rats, are reported here. Materials and Methods In repeat-dose toxicology studies, rats and monkeys received 0, 50, 250, or 1000 IU/kg rFVIIIFc every other day for 4 weeks. In a high-dose tolerance study, monkeys received 1 rFVIIIFc dose of 3000, 10,000, or 20,000 IU/kg. Evaluations included in-life observations, laboratory and post-mortem evaluations, pharmacokinetics, and local tolerance. Allometric scaling, using data from 4 animal species and humans, was used to evaluate the relationship between animal and human pharmacokinetics. Results rFVIIIFc was well tolerated with no adverse toxicological findings directly attributable to rFVIIIFc. As expected, antibodies to this fully human protein developed in rats and monkeys in a time-dependent fashion following repeated dosing, leading to increased clearance in both species. There were no local reactions (infusion site) or evidence of thrombosis at high doses in rats and monkeys. Allometric scaling demonstrated more rapid clearance in small animals compared with humans and a volume of distribution (steady state) proportional to body weight across species, suggesting that animal pharmacokinetics are predictive of human pharmacokinetics. Conclusions Repeated doses of rFVIIIFc in 2 relevant animal species and high doses of rFVIIIFc in monkeys were well tolerated. These results supported the clinical safety of rFVIIIFc observed in phase 1/2a and phase 3 clinical trials. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full Text from ScienceDirect