First-in-human evaluation of anti-von Willebrand factor therapeutic aptamer ARC1779 in healthy volunteers
First-in-human evaluation of anti-von Willebrand factor therapeutic aptamer ARC1779 in healthy volunteers
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DOI：
10.1161/circulationaha.107.724864
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发表时间：
2007-12-04
期刊：
影响因子：
37.8
通讯作者：
Schaub, Robert G.
中科院分区：
文献类型：
--
作者：
Gilbert, James C.;DeFeo-Fraulini, Tia;Schaub, Robert G.
背景- ARC1779是一种治疗性的血管性血友病因子（vWF） A1结构域的适体拮抗剂，vWF是血小板上受体糖蛋白1b的配体。ARC1779是一种用于急性冠状动脉综合征患者的新型抗血栓药物。方法和结果-这是一项随机、双盲、安慰剂对照的研究，在47名健康志愿者中使用剂量为0.05至1.0 mg/kg的ARC1779。通过ELISA检测游离vWF A1结合位点和血小板功能分析仪检测药效学效应。在药代动力学方面，ARC1779的浓度-时间分布呈单相。观察到的浓度与曲线下面积成剂量正比。平均表观消除半衰期约为2小时，平均停留时间约为3小时。平均表观分布体积（稳态和终末期）约为血容量的一半，表明ARC1779分布在中央隔室。平均清除率约为肾小球滤过率的10%至21%，提示肾滤过可能不是ARC1779清除率的主要机制。抑制vWF A1结合活性的EC90值为2.0 μ g/mL (151 nmol/L)，抑制血小板功能的EC90值为2.6 μ g/mL （196 nmol/L）。ARC1779总体耐受性良好，未观察到出血。不良事件往往是轻微的，与剂量无关。结论：这是对一种新型vWF适配体拮抗剂的首次人体评估。ARC1779对vWF活性和血小板功能产生剂量和浓度依赖的抑制作用，其持续时间适合于急性冠状动脉综合征的预期临床应用。
Background - ARC1779 is a therapeutic aptamer antagonist of the A1 domain of von Willebrand Factor (vWF), the ligand for receptor glycoprotein 1b on platelets. ARC1779 is being developed as a novel antithrombotic agent for use in patients with acute coronary syndromes.Methods and Results - This was a randomized, double-blind, placebo-controlled study in 47 healthy volunteers of doses of ARC1779 from 0.05 to 1.0 mg/kg. Pharmacodynamic effects were measured by an ELISA for free vWF A1 binding sites and by a platelet function analyzer. In terms of pharmacokinetics, the concentration-time profile of ARC1779 appeared monophasic. The observed concentration and area under the curve were dose proportional. The mean apparent elimination half-life was approximate to 2 hours, and mean residence time was approximate to 3 hours. The mean apparent volumes of distribution ( at steady state and during terminal phase) were approximately one half the blood volume, suggesting that ARC1779 distribution is in the central compartment. The mean clearance ranged from approximate to 10% to approximate to 21% of the glomerular filtration rate, suggesting that renal filtration may not be a major mechanism of clearance of ARC1779. Inhibition of vWF A1 binding activity was achieved with an EC90 value of 2.0 mu g/mL ( 151 nmol/L) and of platelet function with an EC90 value of 2.6 mu g/mL ( 196 nmol/L). ARC1779 was generally well tolerated, and no bleeding was observed. Adverse events tended to be minor and not dose related.Conclusions - This is the first-in-human evaluation of a novel aptamer antagonist of vWF. ARC1779 produced dose- and concentration-dependent inhibition of vWF activity and platelet function with duration of effect suitable for the intended clinical use in acute coronary syndromes.