A randomised study in healthy volunteers to investigate the safety, tolerability and pharmacokinetics of idarucizumab, a specific antidote to dabigatran
A randomised study in healthy volunteers to investigate the safety, tolerability and pharmacokinetics of idarucizumab, a specific antidote to dabigatran
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DOI：
10.1160/th14-12-1080
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发表时间：
2015-05-01
影响因子：
6.7
通讯作者：
Reilly, Paul
中科院分区：
文献类型：
--
作者：
Glund, Stephan;Moschetti, Viktoria;Reilly, Paul
Idarucizumab是一种与达比加群高亲和力结合的单克隆抗体片段，正在开发中，可作为达比加群的特异性解毒剂。在这项首次人体单次给药剂量递增研究中，我们研究了依达赛珠单抗的药代动力学、安全性和耐受性。18-45岁的健康男性志愿者接受20 mg至8 g依达赛珠单抗，10个连续剂量组1小时静脉输注，或1、2或4 g依达赛珠单抗，5分钟输注。每个剂量组的受试者以3：1的比例随机分配至依达赛珠单抗组或安慰剂组。共有110例随机分配的受试者接受研究药物治疗（安慰剂组27例，依达赛珠单抗组83例）。依达赛珠单抗的峰值和总暴露量随剂量成比例增加。在接近输注结束时达到最大血浆浓度，随后迅速下降，初始依达赛珠单抗半衰期为45分钟。对于5分钟输注，这导致血浆浓度在4小时内降低至低于峰值的5%。Idarucizumab（不存在达比加群）对凝血参数或内源性凝血酶潜力无影响。依达赛珠单抗和安慰剂组的总体不良事件（AE）频率相似，未观察到与依达赛珠单抗剂量的相关性。药物相关AE（主要终点）罕见（发生于2例安慰剂组受试者和3例依达赛珠单抗组受试者），且大多为轻度;均未导致研究中止。总之，依达赛珠单抗的药代动力学特征符合快速达峰暴露和快速消除的要求，对药效学参数无影响。Idarucizumab在健康男性中安全且耐受性良好。
Idarucizumab, a monoclonal antibody fragment that binds dabigatran with high affinity, is in development as a specific antidote for dabigatran. In this first-in-human, single-rising-dose study, we investigated the pharmacokinetics, safety and tolerability of idarucizumab. Healthy male volunteers aged 18-45 years received between 20 mg and 8 g idarucizumab as a 1-hour intravenous infusion in 10 sequential dose groups, or 1, 2 or 4 g idarucizumab as a 5-minute infusion. Subjects within each dose group were randomised 3:1 to idarucizumab or placebo.A total of 110 randomised subjects received study drug (27 placebo, 83 idarucizumab). Peak and total exposure to idarucizumab increased proportionally with dose. Maximum plasma concentrations were achieved near the end of infusion, followed by a rapid decline, with an initial idarucizumab half-life of 45 minutes. For the 5-minute infusions, this resulted in a reduction of plasma concentrations to less than 5% of peak within 4 hours. Idarucizumab (in the absence of dabigatran) had no effect on coagulation parameters or endogenous thrombin potential. Overall adverse event (AE) frequency was similar for idarucizumab and placebo, and no relationship with idarucizumab dose was observed. Drug-related AEs (primary end-point) were rare (occurring in 2 placebo and 3 idarucizumab subjects) and were mostly of mild intensity; none of them resulted in study discontinuation. In conclusion, the pharmacokinetic profile of idarucizumab meets the requirement for rapid peak exposure and rapid elimination, with no effect on pharmacodynamic parameters. Idarucizumab was safe and well tolerated in healthy males.