背景:Idarucizumab是一种人源化单克隆抗体片段,以高亲和力与达比加群特异性结合。
目的:本研究调查了安全性,单独使用idarucizumab和达比加群在稳态下的耐受性和药代动力学,以及idarucizumab对达比加群诱导的抗凝作用。
方法:这是一个两部分,第一阶段,随机化,安慰剂对照,双盲,在健康的日本男性中进行剂量上升试验。部分1:32名受试者(男性)接受单一剂量的idarucizumab(1、2、4或8g[n=6/剂量组])或安慰剂(n=2/剂量组)。第2部分:48名男性接受达比加群(220mgbid),然后接受idarucizumab(n=9/剂量组)1、2、4或5g(2×2.5g),或安慰剂(n=3/剂量组)。抗idarucizumab抗体(ADAs)和idarucizumab对抗凝参数的影响(稀释的凝血酶时间[dTT],ecarin凝血时间[ECT],评估活化的部分凝血活酶时间[aPTT]和凝血酶时间[TT])。
结果:在接受idarucizumab的受试者中未报告不良事件。单剂量的idarucizumab(单独或在达比加群的稳态)后,在每次输注结束时达到最大血浆浓度.在所有剂量组输注伊达卢珠单抗后,所有抗凝参数的平均值立即降至正常上限以下;在整个测量期间,效果持续在4和2×2.5g,直到72小时。在1-和2-g剂量下,部分恢复的抗凝作用发生。单独使用伊达珠单抗对凝血参数没有影响。在接受idarucizumab的6/60男性中出现治疗引起的ADAs。
结论:Idarucizumab输注立即实现,日本志愿者中达比加群诱导的抗凝完全和持续逆转。Idarucizumab耐受性良好,无促凝血作用。试验注册号:ClinicalTrials.govNCT02028780(已完成)。
BACKGROUND: Idarucizumab is a humanized monoclonal antibody fragment that specifically binds with high affinity to dabigatran.
OBJECTIVE: This
study investigated the safety, tolerability and pharmacokinetics of idarucizumab alone and with dabigatran at steady state, and the effects of idarucizumab on dabigatran-induced anticoagulation.
METHODS: This was a two-part, phase I, randomized, placebo-controlled, double-blind, rising-dose
trial in healthy Japanese males. Part 1: 32 subjects (males) received single idarucizumab doses (1, 2, 4 or 8 g [n=6/dose group]) or placebo (n=2/dose group). Part 2: 48 males received dabigatran (220 mg bid) followed by idarucizumab (n=9/dose group) 1, 2, 4 or 5 g (2×2.5 g), or placebo (n=3/dose group). Anti-idarucizumab antibodies (ADAs) and idarucizumab effect on anticoagulation parameters (diluted thrombin time [dTT], ecarin clotting time [ECT], activated partial thromboplastin time [aPTT] and thrombin time [TT]) were assessed.
RESULTS: No adverse events were reported in subjects receiving idarucizumab. After single doses of idarucizumab (alone or at steady state of dabigatran), maximum plasma concentration was achieved around the end of each infusion. Mean all anticoagulation parameters fell below the upper limit of normal immediately after idarucizumab infusion in all dose groups; the effect was sustained at 4 and 2×2.5 g over the entire measurement period until 72 h. At 1- and 2-g doses, partial return of the anticoagulant effect occurred. Idarucizumab alone had no effect on coagulation parameters. Treatment-emergent ADAs occurred in 6/60 males receiving idarucizumab.
CONCLUSIONS: Idarucizumab infusion achieved immediate, complete and sustained reversal of dabigatran-induced anticoagulation in Japanese volunteers. Idarucizumab was well tolerated with no procoagulant effects.
Trial registration number: ClinicalTrials.gov NCT02028780 (completed).