Pharmacokinetic and Safety Profile of Ivabradine in Healthy Chinese Men: A Phase I, Randomized, Open-Label, Increasing Single- and Multiple-Dose Study
Pharmacokinetic and Safety Profile of Ivabradine in Healthy Chinese Men: A Phase I, Randomized, Open-Label, Increasing Single- and Multiple-Dose Study
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DOI：
10.1016/j.clinthera.2013.10.007
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发表时间：
2013-12-01
影响因子：
3.2
通讯作者：
Xu, Li
中科院分区：
文献类型：
--
作者：
Jiang, Juanjuan;Tian, Lei;Xu, Li
背景：伊夫拉定是一种纯降心率药物，通过抑制i(F)起作用，i(F)是一种重要的离子电流，参与窦房结细胞的起搏活动。在2012年欧洲心脏病学会关于心力衰竭的指南中，建议尽管接受了循证剂量的p-受体阻滞剂治疗，但仍存在持续高心率的患者应考虑使用伊夫拉定治疗。目的：本研究的目的是探讨伊夫拉定在中国健康男性中的药代动力学/药效学特性和安全性。方法：本研究I期随机、开放、平行、单剂量和多剂量研究在北京中国医学科学院和北京协和医学院心血管研究所临床药理中心和北京协和医学院附属协和医院进行。健康的非吸烟志愿者被随机分配到3个治疗组中的一个，基于5，10或20毫克的伊夫拉定治疗。单次给药后，分配到3个剂量组的受试者接受重复剂量的伊夫拉定，每天2次，共6天。采用高效液相色谱质谱质谱联用法测定伊夫拉定血药浓度。测量收缩压、舒张压和心率，并进行心电图和动态心电图监测。通过体格和眼科检查、生命体征测量、实验室分析和不良反应监测来评估耐受性。结果：共有36名健康中国男性进入研究。单次给药后，血浆伊夫拉定C-max。AUC随剂量增加近似线性增加，t(1/2)和T-max在各剂量组之间无统计学差异。多次给药后，T-max与单次给药相比无明显变化。重复给药后，t(1/2)、C-max和AUC值显著增加(P<；0.001)。单次给药后，最高剂量组的心率在给药后2小时显著减慢，而重复给药后，3组的心率在给药后2~4小时均显著减慢。重复给药后，5、10和20 mg剂量组的平均心率分别降低12.5(4.8)、12.4(6.9)和20.5(5.8)次/分钟。QTC、收缩压和舒张压以及呼吸频率的变化没有明显的趋势。伊夫拉定在中国健康男性中耐受性良好。结论：在一小部分健康中国男性人群中的研究结果表明，伊夫拉定的PK特性与剂量呈线性关系。在单次和重复口服伊夫拉定后，观察到心率显著减慢。伊夫拉定在研究人群中的耐受性似乎很好。(C)2013年，Elsevier HS Journal，Inc.出版。
Background: Ivabradine is a pure heart rate lowering agent that acts by inhibiting I(f), an important ionic current involved in pacemaker activity in the cells of the sinoatrial node. In the 2012 European Society of Cardiology Guidelines on Heart Failure, it was recommended that patients with a persistently high heart rate, despite treatment with an evidence-based dose of a p-blocker, should be considered for treatment with ivabradine.Objective: The aim of this study was to explore the pharmacokinetic/pharmacodynamic properties and safety profile of ivabradine in healthy Chinese men.Methods: This Phase I, randomized, open-label, parallel-arm, single- and multiple-dose study was conducted at the Clinical Pharmacology Center of the Cardiovascular Institute and Fu Wai Hospital at the Chinese Academy of Medical Sciences & Peking Union Medical College in Beijing, People's Republic of China. Healthy, nonsmoking volunteers were randomly assigned to 1 of 3 treatment groups based on treatment with 5, 10 or 20 mg of ivabradine. After a single dose, the subjects assigned to the 3 dose groups received repeated oral doses of ivabradine BID for 6 days. The plasma concentrations of ivabradine were determined by using a HPLC-MS/MS method. Systolic and diastolic blood pressure and heart rate measurements were taken, and ECG and Holter monitoring was performed. Tolerability was assessed throughout the study by physical and ophthalmologic examinations, vital signs measurement, laboratory analyses, and monitoring of adverse effects.Results: A total of 36 healthy Chinese men were enrolled in the study. After the single dose, plasma ivabradine C-max. and AUC increased approximately linearly with dosage, no statistically significant differences were found in t(1/2) or T-max between the dose groups. After multiple doses, there was no significant change in T-max compared with the results after a single dose. After repeated doses, t(1/2), C-max, and AUC increased significantly (P < 0.001). After a single dose, a significant reduction in heart rate at 2 hours' postdose was observed in the highest dose group, whereas after repeated doses, a significant reduction in heart rate was observed from 2 to 4 hours' postdose for all 3 groups. The mean (SD) heart rate after repeated doses decreased 12.5 (4.8), 12.4 (6.9), and 20.5 (5.8) beats/min for the 5-, 10-, and 20-mg dose groups, respectively. No clear trend in the changes in QTc, systolic and diastolic blood pressures, or respiration rate was observed. Ivabradine was well tolerated in these healthy Chinese men.Conclusions: The results of the study in a small population of healthy Chinese men suggest that the PK properties of ivabradine are linear with respect to dosing. After single and repeated oral administration of ivabradine, a significant decrease in heart rate was observed. Ivabradine appeared well tolerated in the population studied. (C) 2013 Published by Elsevier HS Journals, Inc.