Pharmacokinetic properties of two different recombinant activated factor VII formulations
Pharmacokinetic properties of two different recombinant activated factor VII formulations
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DOI：
10.1111/j.1365-2516.2011.02674.x
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发表时间：
2012-05-01
期刊：
影响因子：
3.9
通讯作者：
Bjerre, J.
中科院分区：
文献类型：
--
作者：
Morfini, M.;Jimenez-Yuste, V.;Bjerre, J.
重组VIIa因子适用于治疗具有抑制剂的A型或B型血友病患者的出血事件； FVII 缺乏症和血小板无力症。本文报道的研究目的是比较在两种不同细胞系和培养基中产生的两种 rFVIIa 制剂之间的药代动力学特征：在无血清培养基中培养的中国仓鼠卵巢细胞 (CHO-rFVIIa) 和在非人血清培养基中培养的幼仓鼠肾细胞 (BHK-rFVIIa)。进行了两项临床试验；一种在健康受试者中进行，另一种在患有先天性血友病 A 或 B 的患者中进行，无论有或没有抑制剂。受试者被招募参加双向交叉试验，并随机接受一定剂量的 CHO-rFVIIa 和 BHK-rFVIIa。健康受试者接受一剂新开发的室温稳定rFVIIa制剂中的90μg CHO-rFVIIa kg-1体重(bw)和一剂90μg BHK-rFVIIa kg-1体重(bw)的原始rFVIIa制剂。血友病患者接受一剂270μg CHO-rFVIIa kg-1和一剂270μg BHK-rFVIIa kg-1，均为室温稳定制剂。试验显示，与 BHK-rFVIIa 相比，给予 CHO-rFVIIa 后 FVII 活性水平更高[血浆浓度时间曲线下面积 (AUC) 更高]。因此，无法建立生物等效性。 FVII 活性水平的差异被认为是两种产品之间不同糖基化模式的结果。无论是使用 CHO-rFVIIa 还是使用单剂量 270 μg kg-1 新开发的室温稳定 rFVIIa 都没有引起任何安全问题。
Recombinant factor VIIa is indicated for treatment of bleeding episodes in patients with haemophilia A or B with inhibitors; in FVII deficiency and in Glanzmanns thrombasthenia. The aim of the study reported here was to compare the pharmacokinetic profiles between two formulations of rFVIIa that are produced in two different cell lines and media: Chinese hamster ovary cells cultured in a serum-free medium (CHO-rFVIIa) and baby hamster kidney cells cultured in a non-human serum-based medium (BHK-rFVIIa). Two clinical trials were performed; one in healthy subjects and the other in patients with congenital haemophilia A or B, with or without inhibitors. Subjects were recruited into a two-way crossover trial and were randomized to receive a dose of CHO-rFVIIa and BHK-rFVIIa. Healthy subjects received one dose of 90 mu g CHO-rFVIIa kg-1 bodyweight (bw) in the newly developed room-temperature stable rFVIIa formulation and one dose of 90 mu g BHK-rFVIIa kg-1 bw, in the original rFVIIa formulation. Patients with haemophilia received one dose of 270 mu g CHO-rFVIIa kg-1 and one dose of 270 mu g BHK-rFVIIa kg-1, both in the room-temperature stable formulation. The trials showed higher FVII activity levels [higher area under the plasma concentrationtime curve (AUC)] following administration of CHO-rFVIIa than after BHK-rFVIIa. Therefore, bioequivalence could not be established. The difference in FVII activity levels is believed to be a result of different glycosylation patterns between the two products. Neither the use of CHO-rFVIIa nor the use of one single dose of 270 mu g kg-1 of the newly developed room-temperature stable rFVIIa raised any safety concerns.