Recombinant human factor IX: Replacement therapy, prophylaxis, and pharmacokinetics in canine hemophilia B
Recombinant human factor IX: Replacement therapy, prophylaxis, and pharmacokinetics in canine hemophilia B
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DOI：
10.1182/blood.v88.7.2603.bloodjournal8872603
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发表时间：
1996-10-01
期刊：
影响因子：
20.3
通讯作者：
Schaub, RG
中科院分区：
文献类型：
--
作者：
Brinkhous, KM;Sigman, JL;Schaub, RG
重组人因子IX （rFIX）自1985年以来一直在转导培养细胞系统中表达。由于rFIX在血友病B患者中的体内试验有限，因此本研究采用Chapel Hill菌株的严重血友病B犬进行。三组血友病犬分别给予50、100或200 IU/kg的rFIX。作为对照，第四组血友病犬接受50 IU/kg的高纯度。血浆源性人FIX （pdFIX）。rFIX和pdFIX的凝血和止血作用与所有比较给药方案相似。根据活性数据，rFIX的消除半衰期为18.9 +/- 2.3小时，pdFIX为17.9 +/- 2.1小时。每日给予rFIX的预防性方案导致血浆FIX的持续治疗水平，并且与单次给予相比，在第5天恢复水平增加了两倍。预防方案使FIX从高到完全恢复的机制可能不仅取决于血管内皮结合位点的饱和程度，还取决于血管内和血管外腔室之间FIX分布平衡的动力学改变。rFIX和pdFIX的药代动力学（PK）参数相似。然而，两种产品在第5天的V-1和V-ss的相对PK值与第1天有很大差异，这可能反映了血浆FIX水平升高时室间FIX平衡的变化。从第14天开始，观察到由人类FIX抗原产生的抗人FIX抗体被给予FIX缺陷犬。rFIX和pdFIX的抗原性具有可比性。尽管rFIX和pdFIX产品的生产过程非常不同，但在血友病B犬的体内测试表明，这些产品的功能行为是相似的；它们对替代疗法和预防非常有效。(C) 1996年由美国血液病学会出版。
Recombinant human factor IX (rFIX) has been expressed in transduced cultured cell systems since 1985. Because there has been limited in vivo testing of rFIX in hemophilia B subjects, this study was undertaken using the severe hemophilia B canines of the Chapel Hill strain. Three groups of hemophilic dogs received either 50, 100, or 200 IU/kg of rFIX. As a control, a fourth group of hemophilic dogs received 50 IU/kg of a high purity. plasma-derived human FIX (pdFIX). The coagulant and hemostatic effects of rFIX and pdFIX were similar with all comparative dosing regimens. Based on activity data, the elimination half-life of rFIX was 18.9 +/- 2.3 hours and pdFIX was 17.9 +/- 2.1 hours. A prophylactic regimen administering rFIX daily resulted in a continuous therapeutic level of plasma FIX and was accompanied by a twofold increase in recovery levels by day 5, compared to that observed with administration of a single bolus. The mechanisms of the high to complete recovery of FIX with the prophylactic regimen could depend not only on the degree of saturation of the vascular endothelial binding sites but also on the altered dynamics of the balance of FIX distribution between the intravascular and extravascular compartments. The pharmacokinetic (PK) parameters for rFIX and pdFIX were similar. However, the relative PK values for V-1 and V-ss of both products on day 5 differed greatly from day 1 and may reflect the changing equilibrium of FIX between compartments with elevated levels of plasma FIX. Neutralizing antihuman FIX antibodies resulting from human FIX antigen being administered to FIX deficient dogs were observed beginning at 14 days. The antigenicity of rFIX and pdFIX appeared to be comparable. Despite the very different procedures used for production of rFIX and pdFIX products, in vivo testing in hemophilia B dogs showed the functional behavior of these products is similar; they are highly effective for replacement therapy and for prophylaxis. (C) 1996 by The American Society of Hematology.