A randomized, repeat-dose, pharmacodynamic and safety study of an antidote-controlled factor IXa inhibitor
A randomized, repeat-dose, pharmacodynamic and safety study of an antidote-controlled factor IXa inhibitor
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DOI：
10.1111/j.1538-7836.2008.02932.x
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发表时间：
2008-05-01
影响因子：
10.4
通讯作者：
Becker, R. C.
中科院分区：
文献类型：
--
作者：
Chan, M. Y.;Rusconi, C. P.;Becker, R. C.
背景：积极、安全的抗凝治疗可逆性在临床护理中尚未得到满足。因子IXa是血小板表面快速凝血酶生成所必需的，是调节凝血的新靶点。REG1由RB006（药物）和RB007（解毒剂）组成。核糖核酸适配体RB006通过选择性结合FIXa发挥其抗凝血作用。互补寡核苷酸解毒剂RB007通过沃森-克里克碱基配对与RB006结合，中和其抗fixa活性。目的：考察REG1多次重复给药的安全性、个体内药效学重现性和分级活性可逆性。方法：我们随机选择39名健康志愿者，接受三个连续的体重调整、药物解毒剂治疗周期或双重安慰剂。每个治疗周期包括静脉注射0.75 mg kg(-1) RB006，然后在60分钟后使用递减剂量的RB007，解药/药物比为2:1至0.125:1 （1.5 mg kg（-1）至0.094 mg kg(-1) RB007）。随机分组后14天进行一系列临床评估和凝血测量。结果：重复剂量的RB006获得了高度可重复的活化部分凝血酶活时间（APTT）水平，具有低受试者内变异性（变异系数5.5%，15分钟后组内相关系数5.8），而重复剂量的RB007逆转了APTT水平，具有剂量依赖性和可重复性。没有大出血，也没有其他严重的不良事件。结论：这是首个证明RNA适体-寡核苷酸解毒剂对多重重复剂量安全性、个体内药效学可重复性和分级活性可逆性的人体研究。该结果为研究将这种新型抗凝平台转化为广泛的临床应用奠定了基础。
Background: Active and safe reversibility of anticoagulation is an unmet need in clinical care. Factor IXa, required for rapid thrombin generation on platelet surfaces, is a novel target for modulating coagulation. REG1 comprises RB006 (drug) and RB007 (antidote). RB006, a ribonucleic acid aptamer, exerts its anticoagulant effect by selectively binding FIXa. RB007, the complementary oligonucleotide antidote, binds to RB006 by Watson-Crick base pairing, neutralizing its anti-FIXa activity. Objective: To test the multiple repeat-dose safety, intraindividual pharmacodynamic reproducibility and graded active reversibility of REG1. Methods: We randomized 39 healthy volunteers to receive either three consecutive weight-adjusted, drug-antidote treatment cycles, or double placebo. Each treatment cycle included an intravenous bolus of 0.75 mg kg(-1) RB006, followed 60 min later by a descending dose of RB007, ranging from a 2 : 1 to 0.125 : 1 antidote/drug ratio (1.5 mg kg(-1) to 0.094 mg kg(-1) RB007). Serial clinical assessments and coagulation measurements were performed through 14 days postrandomization. Results: Repeat doses of RB006 achieved highly reproducible activated partial thromboplastin time (APTT) levels with low intrasubject variability (coefficient of variation 5.5%, intraclass correlation coefficient 5.8 at 15 min postdose), while repeat doses of RB007 reversed the APTT levels dose-dependently and reproducibly. There was no major bleeding and there were no other serious adverse events. Conclusions: This is the first human study demonstrating multiple repeat-dose safety, intraindividual pharmacodynamic reproducibility and graded active reversibility of an RNA aptamer-oligonucleotide antidote pair. The results lay the foundation for studying the translation of this novel anticoagulation platform to a wide variety of clinical applications.