Preclinical pharmacology of albumin-free B-domain deleted recombinant factor VIII
Preclinical pharmacology of albumin-free B-domain deleted recombinant factor VIII
复制标题
DOI：
10.1055/s-2002-32661
复制
发表时间：
2002-06-01
影响因子：
5.7
通讯作者：
Mikaelsson, M
中科院分区：
文献类型：
--
作者：
Brinkhous, K;Sandberg, H;Mikaelsson, M
第二代重组因子VIII分子被开发为无白蛋白的配方。在因子VIII的这种修饰形式中，B-结构域的N-末端和C-末端部分被保留并在丝氨酸743和谷氨酰胺1638处融合，导致B-结构域缺失的因子VIII蛋白被称为ReFacto(R)(Genetics Institute，Andover，MA)。ReFacto的临床前研究重点是该产品对血友病A患者群体的疗效。雷法托纠正血友病A犬止血缺陷的疗效和药代动力学与血源性因子相似。经大小排斥层析证实，ReFacto和血浆衍生的人第VIII因子(Octonativ-M7(R)，瑞典，法玛西亚)在输入血友病A犬后都与von Willebrand因子(VWF)有关。输注ReFacto或Octonativ-M7可迅速纠正凝血因子VIII活性(FVIIIc)、全血凝固时间(WBCT)和激活的部分凝血活酶时间(APTT)。ReFacto和Octonativ-M7之间没有明显差异。ReFacto和Octonativ-M7治疗将二次出血时间减少到不到6分钟。与ReFacto相比，血浆衍生因子VIII的清除更快，稳态分布体积更大。Octonativ-M7和ReFacto的半衰期相似。这些数据预测，ReFacto将有效地纠正人类第八因子缺乏状态。
A second-generation recombinant factor VIII molecule was developed with an albumin-free formulation. In this modified form of factor VIII, the N- and C-terminal sections of the B-domain are retained and fused at serine 743 and glutamine 1638, resulting in a B-domain deleted factor VIII protein known as ReFacto(R) (Genetics Institute, Andover, MA). Preclinical studies of ReFacto have focused on efficacy of the product for the hemophilia A patient population. The efficacy and pharmacokinetic profiles of ReFacto were similar to plasma-derived factor VIII in correcting the hemostatic defect of hemophilia A dogs. Both ReFacto and plasma-derived human factor VIII (Octonativ-M7(R), Pharmacia, Stockholm, Sweden) were found to associate with von Willebrand factor (vWF) after infusion into hemophilia A dogs as demonstrated by size exclusion chromatography. Infusion of either ReFacto or Octonativ-M7 quickly corrected factor VIII coagulant activity (FVIIIc), whole blood clotting time (WBCT), and activated partial thromboplastin time (aPTT). No obvious differences were seen between ReFacto and Octonativ-M7. Both ReFacto and Octonativ-M7 treatment reduced secondary, bleeding time to less than 6 minutes. The clearance was faster and the volume of distribution at steady state was larger for plasma-derived factor VIII compared with ReFacto. The half-life was similar between Octonativ-M7 and ReFacto. These data predict that ReFacto will be effective in correcting human factor VIII deficiency states.