Evaluation of Pharmacokinetic and Pharmacodynamic Profiles and Tolerability After Single (2.5, 5, or 10 mg) and Repeated (2.5, 5, or 10 mg BID for 4.5 days) Oral Administration of Ivabradine in Healthy Male Korean Volunteers
Evaluation of Pharmacokinetic and Pharmacodynamic Profiles and Tolerability After Single (2.5, 5, or 10 mg) and Repeated (2.5, 5, or 10 mg BID for 4.5 days) Oral Administration of Ivabradine in Healthy Male Korean Volunteers
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DOI：
10.1016/j.clinthera.2013.04.012
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发表时间：
2013-06-01
影响因子：
3.2
通讯作者：
Lim, Hyeong-Seok
中科院分区：
文献类型：
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作者：
Choi, Hee Youn;Noh, Yook-Hwan;Lim, Hyeong-Seok
背景资料：伊伐布雷定是一种选择性窦房结起搏电流抑制剂，具有降低心率（HR）的作用，具有抗缺血疗效，并可改善心力衰竭结局。目的：本研究的目的是在健康男性韩国志愿者中探索药代动力学（PK）和药效学（PD）特征和耐受性，以及将其与白色受试者的PK/PD曲线进行比较。方法：这是一项在健康男性受试者中进行的随机、双盲、安慰剂对照的I期研究。对于3个给药组中的每一个，9例受试者随机接受伊伐布雷定，3例接受安慰剂。受试者接受伊伐布雷定2.5、5或10 mg单次口服给药，3天洗脱期后，重复给予2.5、5或10 mg BID，持续4.5天。在每个阶段的72小时内采集血液和尿液样本，使用经验证的LC-MS/MS测定伊伐布雷定及其代谢产物S18982的水平，然后进行非房室PK分析。对于PD特性和耐受性，获得24小时霍尔特记录：基线、单次给药后、重复给药后和末次给药后。系列静息12导联心电图评估也进行了整个study.Results：48例受试者参加，45完成了研究。2.5、5和10 mg单次给药后，伊伐布雷定的平均C-max水平分别为9、15和39 ng/mL，平均AUC（0-last）值分别为30、52和121 ng。h/mL。稳态时，所有3种剂量的平均C-max、C-ss水平分别为11、19和42 ng/mL，在中位Tmax 0.67小时时达到。平均AUC（0-tau）水平为43、58和139 ng。h/mL。PK结果与剂量和时间呈线性关系。与安慰剂组相比，在所有伊伐布雷定组中均观察到霍尔特记录和ECG的平均HR降低。重复给药后，HR的平均降幅大于同一时期单次给药的降幅。在5 mg和10 mg伊伐布雷定组与安慰剂组之间观察到统计学显著性差异。在2例接受伊伐布雷定的受试者中共报告了3起不良事件;均完全恢复，无后遗症。结论：这些健康的韩国男性志愿者对伊伐布雷定的单次和重复给药耐受性良好。伊伐布雷定诱导HR显著降低，尤其是在5 mg和10 mg剂量下。PK/PD特征与白色受试者相似，表明韩国和白色受试者之间伊伐布雷定的剂量浓度反应关系相似。
Background: Ivabradine, a selective inhibitor of the pacemaker current in the sinoatrial node, has shown pure heart rate (HR)-reducing effects with anti-ischemic efficacy as well as improvement in heart failure outcomes.Objective: The purpose of this study was to explore pharmacokinetic (PK) and pharmacodynamic (PD) characteristics and tolerability in healthy male Korean volunteers, as well as to compare them with PK/PD profiles of white subjects.Methods: This was a randomized, double-blind, placebo-controlled Phase I study conducted in healthy male subjects. For each of the 3 dosing groups, 9 subjects were randomized to receive ivabradine and 3 to receive placebo. Subjects received a single oral dose of ivabradine 2.5, 5, or 10 mg and after a 3-day washout period, repeat doses of 2.5, 5, or 10 mg BID for 4.5 days. Blood and urine samples were collected over 72 hours during each period, and levels of ivabradine and its metabolite S18982 were determined by using validated LC-MS/MS, followed by noncompartmental PK analysis. For PD properties and tolerability, 24-hour Holter recordings were obtained: at baseline, after a single dose, after repeated doses, and after the last dose. Serial resting 12-lead ECG assessments were also performed throughout the study.Results: Forty-eight subjects were enrolled, and 45 completed the study. After single doses of 2.5, 5, and 10 mg, respective mean C-max levels of ivabradine were 9, 15, and 39 ng/mL, and mean AUC(0-last) values were 30, 52, and 121 ng . h/mL. At steady state, mean C-max,C-ss levels were 11, 19, and 42 ng/mL, reached at a median T-max of 0.67 hour for all 3 doses. The mean AUC(0-tau) levels were 43, 58, and 139 ng . h/mL, respectively. The PK findings were linear with dose and time. Decreases in mean HR on both the Holter recordings and ECGs were observed in all of the ivabradine groups compared with placebo. After die repeated doses, mean decreases in HR were greater than those for the single doses for the same period. Statistically significant differences were observed between the 5- and 10-mg ivabradine groups and placebo. A total of 3 adverse events were reported in 2 subjects receiving ivabradine; both fully recovered without sequelae.Conclusions: Single and repeated administration of ivabradine were generally well tolerated in these healthy male Korean volunteers. Ivabradine induced significant reductions in HR, especially at doses of 5 and 10 mg. PK/PD characteristics were similar to those found in white subjects, suggesting that the dose concentration response relationship of ivabradine is similar between Korean and white subjects.