盐酸替利定的药代动力学、安全性和耐受性，一种新型二氢吡啶类双重 L/T 型钙通道阻滞剂，在健康中国受试者中单剂量和多剂量口服后的情况。
Pharmacokinetics, Safety and Tolerability of Tylerdipine Hydrochloride, a Novel Dihydropyridine Dual L/T-type Calcium Channel Blocker, after Single and Multiple Oral Doses in Healthy Chinese Subjects.
机构信息
Phase I Clinical Trial Unit, The First Affiliated Hospital with Nanjing Medical University, #300 Guangzhou Road, Nanjing, 210029, Jiangsu, China.
出版信息
Clin Drug Investig. 2019 Jan;39(1):85-96. doi: 10.1007/s40261-018-0722-5.
BACKGROUND AND OBJECTIVE
Tylerdipine hydrochloride (KBP-5660) is a novel L/T-type dual calcium channel blocker developed for the treatment of hypertension. We aimed to study the pharmacokinetics, safety and tolerability of tylerdipine in healthy Chinese subjects.
METHODS
Two double-blind, randomized, dose-escalation studies were conducted that included a total of 88 healthy subjects: (1) a single-ascending dose (SAD) study; and (2) a multiple-ascending dose (MAD) study. In the SAD study, 64 subjects were randomly assigned to receive a single dose of 0.5, 2.5, 5, 10, 15, 20, 25, or 30 mg of tylerdipine or placebo. In the MAD study, 24 subjects were randomly assigned to receive 10 or 20 mg of tylerdipine or placebo once daily for 9 days. Blood samples were collected at the designated time points for pharmacokinetic analyses. Safety assessments were conducted throughout the study.
RESULTS
Following a single oral dose of tylerdipine of 5-30 mg, the mean maximum plasma concentration (C) increased from 0.9993 to 10.11 ng/ml; mean area under the plasma-concentration curve (AUC) from time zero to 72 h increased from 4.332 to 73.95 h·ng/ml. AUC increased in a greater than dose-proportional manner, whereas C exhibited a rough but non-typical dose-proportionality increase. In the MAD study, steady-state conditions were achieved after 1 week of daily dosing in both dose groups. Accumulation of tylerdipine was low, with accumulation ratios (R) of less than 1.65. All adverse events were assessed as mild or moderate.
CONCLUSION
Tylerdipine hydrochloride was safe and well tolerated. The exposure (AUC) of tylerdipine over the dose range of 5-30 mg increased in a greater than dose-proportional manner, while C exhibited a rough but non-typical dose proportionality increase. A slight accumulation of tylerdipine was observed following multiple dosing.
STUDY REGISTRATIONS
CTR20140862 and CTR20150660.
背景和目的
盐酸替利定（KBP-5660）是一种新型 L/T 型双钙通道阻滞剂，用于治疗高血压。我们旨在研究替利定在健康中国受试者中的药代动力学、安全性和耐受性。
方法
进行了两项双盲、随机、剂量递增研究，共纳入 88 名健康受试者：（1）单次递增剂量（SAD）研究；（2）多次递增剂量（MAD）研究。在 SAD 研究中，64 名受试者随机分为单次接受 0.5、2.5、5、10、15、20、25 或 30mg 替利定或安慰剂。在 MAD 研究中，24 名受试者随机分为每日接受 10 或 20mg 替利定或安慰剂一次，共 9 天。在指定时间点采集血样进行药代动力学分析。整个研究过程中进行安全性评估。
结果
单次口服替利定 5-30mg 后，平均最大血浆浓度（C）从 0.9993 增加到 10.11ng/ml；从 0 到 72h 的平均血浆浓度-时间曲线下面积（AUC）从 4.332 增加到 73.95h·ng/ml。AUC 呈大于剂量比例增加，而 C 呈粗糙但非典型的剂量比例增加。在 MAD 研究中，两组在每日给药 1 周后均达到稳态。替利定的蓄积率（R）低于 1.65，蓄积较低。所有不良事件均评估为轻度或中度。
结论
盐酸替利定安全且耐受性良好。替利定在 5-30mg 剂量范围内的暴露（AUC）呈大于剂量比例增加，而 C 呈粗糙但非典型的剂量比例增加。多次给药后观察到替利定略有蓄积。
研究注册
CTR20140862 和 CTR20150660。
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