Dumont Jennifer A, Loveday Kenneth S, Light David R, Pierce Glenn F, Jiang Haiyan
Biogen, Cambridge, MA, USA.
Thromb Res. 2015 Dec;136(6):1266-72. doi: 10.1016/j.thromres.2015.07.019. Epub 2015 Jul 23.
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.
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.
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.
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.
重组因子VIII Fc融合蛋白（rFVIIIFc）是一种新型重组因子VIII，半衰期延长，用于治疗甲型血友病。本文报道了评估rFVIIIFc在两种药理学相关物种（食蟹猴和Sprague Dawley大鼠）中毒理学作用的研究。
在重复剂量毒理学研究中，大鼠和猴子每隔一天接受0、50、250或1000 IU/kg的rFVIIIFc，持续4周。在高剂量耐受性研究中，猴子接受3000、10000或20000 IU/kg的1剂rFVIIIFc。评估包括活体观察、实验室和死后评估、药代动力学和局部耐受性。使用来自4种动物物种和人类的数据进行异速生长标度，以评估动物和人类药代动力学之间的关系。
rFVIIIFc耐受性良好，没有直接归因于rFVIIIFc的不良毒理学发现。正如预期的那样，在重复给药后，大鼠和猴子体内针对这种完全人源蛋白的抗体呈时间依赖性产生，导致两种物种的清除率增加。大鼠和猴子在高剂量时没有局部反应（输注部位）或血栓形成的证据。异速生长标度表明，与人类相比，小动物的清除速度更快，且分布容积（稳态）与物种体重成正比，这表明动物药代动力学可预测人类药代动力学。
在两种相关动物物种中重复给予rFVIIIFc以及在猴子中给予高剂量rFVIIIFc耐受性良好。这些结果支持了在1/2a期和3期临床试验中观察到的rFVIIIFc的临床安全性。
