一种我国自主研发rhFⅧ的临床前药代动力学初步比较研究

A preliminary comparison on pharmacokinetics between a domestic rhFⅧ and a commercial drag xynthain hemophilia A mice

目的初步研究具有自主知识产权的重组表达人凝血因子(rFⅧ)在研品种的临床前药代动力学。方法建立并优化生色底物活性检测方法,用于测定血浆样品中FⅧ活性浓度(FⅧ∶C);选择市售进口的同类药物Xyntha为参比药物,对只敲除了FⅧ基因的模型小鼠(HA小鼠)分组(n=18)单次尾静脉注射280 IU·kg-1受试药rhFⅧ或参比药Xyntha,在0、0.083、1、3、6、9、24、36和48 h采集血浆样品(30μL/只,每个时间点6个样品),测定其FⅧ∶C并计算药代动力学参数。结果受试rhFⅧ组和参比药Xyntha组给药后,0.083、1、3、6、9、24、36和48 h的血浆FⅧ∶C(IU·mL-1)分别为3.218±1.511 vs 3.616±1.504、2.089±0.593 vs 2.786±1.157、1.953±0.546 vs1.942±0.807、0.613±0.360 vs 1.025±0.321、0.515±0.370 vs 0.894±0.297、0.187±0.082 vs 0.310±0.108、0.061±0.038 vs 0.115±0.040、0.043±0.042 vs 0.023±0.012(P>0.05);主要药代动力学参数:t1/2(h)分别为8.83 vs9.15,AUC0-t(h·IU·mL-1)分别为19.67 vs 27.70,Vd(mL·kg-1)分别为176.37 vs 132.00,CL(mL·h-1·kg-1)分别为13.85 vs 10.00,MRT0-t(h)分别为8.64 vs 9.62。结论受试rhFⅧ单次HA小鼠尾静脉给药280 IU·kg-1后在小鼠体内的药代动力学过程与市售同类进口药物Xyntha基本一致。

Objective： To perform a preliminary study of preclinical pharmacokinetics of a domestic recombinant human coagulation factor Ⅷ（ rhFⅧ）. Methods A chromogenic activity assay to determine the plasma FⅧ∶ C activity was established and optimized. A commercially available rFⅧ product,Xyntha,was selected to be the reference drug. Hemophilia A mice were i. v. administrated of 280 IU·kg- 1rhFⅧ or Xynthaand the blood samples（ 30 μL /each mice,six blood samples per time point） were collected from the orbital plexus in the interval of 0,0. 083,1,3,6,9,24,36 and 48 h post-administration. The FⅧ∶ C level of blood samples were assayed and then the pharmacokinetic parameters were calculated. Results The FⅧ： C level of blood samples on different time points（ 0. 083,1,3,6,9,24,36,48 h） were 3. 218 ± 1. 511 vs 3. 616 ±1. 504,2. 089 ± 0. 593 vs 2. 786 ± 1. 157,1. 953 ± 0. 546 vs 1. 942 ± 0. 807,0. 613 ± 0. 360 vs 1. 025 ± 0. 321,0. 515 ± 0. 370vs 0. 894 ± 0. 297,0. 187 ± 0. 082 vs 0. 310 ± 0. 108,0. 061 ± 0. 038 vs 0. 115 ± 0. 040,0. 043 ± 0. 042 vs 0. 023 ± 0. 012 IU·mL- 1（ P〉 0.05） after administration of 280 IU·kg- 1rhFⅧ and Xyntharespectively. the main pharmacokinetic parameters were as follows： the t1 /2（ h） were 8.83 vs 9.15,AUC0-t（ h·IU·mL- 1） were 19.67 vs 27.70,Vd were 176.37 vs132. 00 mL·kg- 1,CL（ mL·h- 1·kg- 1） were 13.85 vs 10.00,MRT0-t（ h） were 8.64 and 9.62 for rhFⅧ and Xyntha,respectively. Conclusion Comparing with the commercial drug Xyntha,the rhFⅧ has the similar and comparable pharmacokinetics performance in the HA mice after a single intravenous administration of 280 IU·kg- 1.