Effect of Age and Renal Function on Idarucizumab Pharmacokinetics and Idarucizumab-Mediated Reversal of Dabigatran Anticoagulant Activity in a Randomized, Double-Blind, Crossover Phase Ib Study.
Effect of Age and Renal Function on Idarucizumab Pharmacokinetics and Idarucizumab-Mediated Reversal of Dabigatran Anticoagulant Activity in a Randomized, Double-Blind, Crossover Phase Ib Study.
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年龄和肾功能对iDarucizumab药代动力学以及iDarucizumab介导的dabigatran抗凝活性的逆转在随机的，双盲的IB研究中。
DOI：
10.1007/s40262-016-0417-0
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发表时间：
2017-01
影响因子：
4.5
通讯作者：
Kreuzer J
中科院分区：
文献类型：
--
作者：
Glund S;Stangier J;van Ryn J;Schmohl M;Moschetti V;Haazen W;De Smet M;Gansser D;Norris S;Lang B;Reilly P;Kreuzer J
Idarucizumab是一种特异性逆转达比加群介导的抗凝作用的抗体片段。在达比加群治疗的中年、老年和肾损害志愿者中研究了依达赛珠单抗的安全性、药代动力学和药效学，这些志愿者的特征与接受抗凝治疗的患者相似。在这项随机化、双盲、交叉研究中，46例受试者（12例中年受试者，45-64岁; 16例老年受试者，65-80岁; 18例轻度或中度肾损害受试者）接受达比加群酯（DE; 220或150 mg，每日两次）治疗4天。在稳态DE后约2小时，以1、2.5和5 g或2 × 2.5 g间隔1小时的剂量或安慰剂快速（5分钟）输注给予Idarucizumab。在所有组中，达比加群延长的稀释凝血酶时间、埃卡林凝血时间和活化部分凝血活酶时间在依达赛珠单抗输注后立即逆转至基线。剂量≥2.5 g时可持续缓解。在所有条件下，依达赛珠单抗的耐受性良好。未观察到年龄对依达赛珠单抗药代动力学的影响;然而，与健康中年受试者相比，轻度或中度肾损害受试者的依达赛珠单抗暴露量增加（高达84%）、清除率降低和初始半衰期延长（高达49%）。肾功能损害与依达赛珠单抗暴露量增加和清除率降低相关。Idarucizumab可立即、完全和持续逆转达比加群抗凝活性，在中年、老年和肾损害志愿者中安全且耐受性良好。结果支持5 g剂量依达赛珠单抗的临床使用。 http://www.clinicaltrials.gov唯一标识符：NCT 01955720。本文的在线版本（doi：10.1007/s40262-016-0417-0）包含补充材料，可供授权用户使用。
Idarucizumab is an antibody fragment that specifically reverses dabigatran-mediated anticoagulation. Safety, pharmacokinetics and pharmacodynamics of idarucizumab were investigated in dabigatran-treated, middle-aged, elderly and renally impaired volunteers with characteristics similar to patients receiving anticoagulant therapy. In this randomized, double-blind, crossover study, 46 subjects (12 middle-aged, 45–64 years; 16 elderly, 65–80 years; and 18 with mild or moderate renal impairment) received dabigatran etexilate (DE; 220 or 150 mg twice daily) for 4 days. Idarucizumab doses of 1, 2.5 and 5 g or 2 × 2.5 g 1 h apart, or placebo, were administered as a rapid (5 min) infusion ~2 h after DE at steady state. Dabigatran-prolonged diluted thrombin time, ecarin clotting time and activated partial thromboplastin time were reversed to baseline immediately after idarucizumab infusion in all groups. Reversal was sustained with doses ≥2.5 g. Idarucizumab was well tolerated under all conditions. No impact of age on idarucizumab pharmacokinetics was observed; however, subjects with mild or moderate renal impairment demonstrated increased exposure (up to 84 %), decreased clearance and prolonged (by up to 49 %) initial half-life of idarucizumab compared with healthy middle-aged subjects. Impaired renal function was associated with increased exposure and decreased clearance of idarucizumab. Idarucizumab resulted in immediate, complete and sustained reversal of dabigatran anticoagulant activity, and was safe and well tolerated in middle-aged, elderly and renally impaired volunteers. The results support the clinical use of a 5 g dose of idarucizumab. http://www.clinicaltrials.gov. Unique identifier: NCT01955720. The online version of this article (doi:10.1007/s40262-016-0417-0) contains supplementary material, which is available to authorized users.