达比加群酯在中国健康受试者中单次和多次口服给药的药代动力学和安全性。
Pharmacokinetics and Safety of Dabigatran Etexilate after Single and Multiple Oral Doses in Healthy Chinese Subjects.
机构信息
Department of Pharmacy, Peking University Third Hospital, Peking, China.
Department of Pharmacy, Peking University International Hospital, No. 1 Life Park Road, Life Science Park of Zhongguancun, Changping District, Peking, 102206, China.
出版信息
Eur J Drug Metab Pharmacokinet. 2020 Oct;45(5):601-609. doi: 10.1007/s13318-020-00626-4.
BACKGROUND AND OBJECTIVE
Dabigatran etexilate is a non-vitamin K antagonist oral anticoagulant (NOAC) that is used to prevent stroke and systemic embolism in adults with nonvalvular atrial fibrillation (NVAF) and one or more risk factors. Pharmacokinetic data on this anticoagulant in Chinese subjects are limited. This study aimed to provide further information on the pharmacokinetic profile of dabigatran in healthy Chinese subjects, together with its safety profile.
METHODS
This was an open-label, single-centre, phase I study. Subjects were randomized into 110 and 150 mg dabigatran etexilate treatment groups. Each subject received 7 days of treatment: a single dose on day 1, no dose on days 2-3, and then multiple doses on days 4-10. Blood samples were collected to analyze the pharmacokinetic profile of dabigatran. All adverse events (AEs) were recorded. Routine clinical laboratory tests, a physical examination, vital signs, and 12-lead electrocardiogram (ECG) measurements were performed.
RESULTS
A total of 28 subjects (14 males and 14 females) were randomized in this trial. The plasma concentration of total dabigatran reached its maximum measured concentration at a median time of 3-4 h from the dose of interest (either the initial single dose on day 1 or the final dose on day 10) under fed conditions, and declined with an elimination half-life of 10.7-10.9 h following the dose of interest. There was a modest difference in pharmacokinetic profile between male and female subjects. None of the subjects experienced a serious adverse event (SAE) or an AE of moderate or severe intensity. The investigator reported that 17 of the 28 subjects had mild treatment-emergent AEs that resolved without any concomitant treatment or intervention. No clinically significant changes in vital signs or ECG parameters were observed.
CONCLUSIONS
This study revealed the pharmacokinetic characteristics and good safety profile of dabigatran in healthy Chinese subjects.
背景和目的
达比加群酯是一种非维生素 K 拮抗剂口服抗凝药（NOAC），用于预防非瓣膜性心房颤动（NVAF）伴或不伴一个或多个危险因素的成人中风和全身性栓塞。在中国受试者中，关于这种抗凝剂的药代动力学数据有限。本研究旨在进一步提供达比加群酯在健康中国受试者中的药代动力学特征及其安全性特征的信息。
方法
这是一项开放标签、单中心、I 期研究。受试者随机分为 110 和 150mg 达比加群酯治疗组。每个受试者接受 7 天的治疗：第 1 天单次剂量，第 2-3 天无剂量，然后第 4-10 天多次剂量。采集血样以分析达比加群酯的药代动力学特征。记录所有不良事件（AE）。进行常规临床实验室检查、体格检查、生命体征和 12 导联心电图（ECG）测量。
结果
本试验共纳入 28 名受试者（14 名男性和 14 名女性）。在进食条件下，总达比加群的血浆浓度在给药后 3-4 小时达到最大测量浓度，中位数时间（无论是第 1 天的初始单次剂量还是第 10 天的最后剂量），在剂量后半衰期为 10.7-10.9 小时。男女受试者的药代动力学特征略有差异。无受试者发生严重不良事件（SAE）或中度或重度强度的 AE。研究者报告 28 名受试者中有 17 名出现轻度治疗后出现的 AE，无需任何伴随治疗或干预即可缓解。未观察到生命体征或心电图参数有临床意义的变化。
结论
本研究揭示了达比加群酯在健康中国受试者中的药代动力学特征和良好的安全性特征。
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