Pharmacokinetics and safety of fibrinogen concentrate
Pharmacokinetics and safety of fibrinogen concentrate
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DOI：
10.1111/j.1538-7836.2009.03633.x
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发表时间：
2009-12-01
影响因子：
10.4
通讯作者：
Mannucci, P.
中科院分区：
文献类型：
--
作者：
Manco-Johnson, M. J.;Dimichele, D.;Mannucci, P.
背景资料：尽管纤维蛋白原浓缩物已用于治疗先天性纤维蛋白原缺乏症多年，但其药代动力学知识仅来自两项小型研究。目的：在无纤维蛋白原血症患者中评估纤维蛋白原浓缩物（人）（FCH）的药代动力学（PK）特征、凝块完整性和安全性。患者和方法：在美国和意大利对年龄≥ 6岁的无纤维蛋白原血症患者进行了一项多国、前瞻性、开放标签、非对照研究。在输注前后采集血浆，用于PK分析，并通过旋转血栓弹性测定法评价最大凝块硬度（MCF），以评估凝块完整性。根据不良事件和实验室参数评估安全性。结果：单次给药70 mg kg-1体重（b.w.）在14例患者中，FCH的中位增量体内恢复为每mg kg-1体重增加1.7 mg dL-1，输注后1 h，纤维蛋白原活性和抗原的中位水平为1.3 g L-1。纤维蛋白原活性的中位半衰期（t（1/2））为77.1 h，抗原为88.0 h。< 16岁儿童的血浆回收率与16至< 65岁成人相似，但t（1/2）和曲线下面积降低，稳态容量和清除率增加。输注FCH后1 h，MCF较基线平均增加8.9 mm（P < 0.0001）。报告的所有4起不良事件均为轻度，无严重事件或与研究药物相关。结论：这些PK结果证实了FCH输注后血浆纤维蛋白原水平迅速升高。结合血凝块完整性和安全性数据以及已发表的有效性数据，结果支持FCH替代可恢复止血且安全性良好的观点。
Background: Although fibrinogen concentrate has been available for the treatment of congenital fibrinogen deficiency for years, knowledge of its pharmacokinetics comes from only two small studies. Objectives: To assess the pharmacokinetic (PK) profile, clot integrity and safety of fibrinogen concentrate (human) (FCH) in patients with afibrinogenemia. Patients and methods: A multinational, prospective, open-label, uncontrolled study of patients with afibrinogenemia >= 6 years of age was conducted in the USA and Italy. Plasma was collected before and after infusion for PK analyses and evaluation by rotational thromboelastometry of maximum clot firmness (MCF) to assess clot integrity. Safety was assessed on the basis of adverse events and laboratory parameters. Results: After a single dose of 70 mg kg-1 body weight (b.w.) FCH in 14 patients, median incremental in vivo recovery was a 1.7 mg dL-1 increase per mg kg-1 b.w., and median levels were 1.3 g L-1 for fibrinogen activity and antigen 1 h after infusion. Median half-life (t(1/2)) was 77.1 h for fibrinogen activity and 88.0 h for antigen. Plasma recovery in children < 16 years old was similar to that in adults aged 16 to < 65 years, but the t(1/2) and area under the curve were decreased, with an increased steady-state volume and clearance. MCF increased by a mean of 8.9 mm from baseline to 1 h after infusion of FCH (P < 0.0001). All four adverse events reported were mild, and none was serious or related to study drug. Conclusions: These PK findings confirm a rapid increase in plasma fibrinogen levels after infusion with FCH. Together with the clot integrity and safety data and published data on efficacy, the results support the idea that FCH substitution can restore hemostasis with a good safety profile.