Influence of Renal Impairment on the Pharmacokinetics and Pharmacodynamics of Oral Dabigatran Etexilate
Influence of Renal Impairment on the Pharmacokinetics and Pharmacodynamics of Oral Dabigatran Etexilate
复制标题
肾功能损害对口服达比加群酯药代动力学和药效学的影响
作者：
J. Stangier;K. Rathgen;H. Stähle;D. Mazur
背景与目的：达比加群酯是一种口服直接凝血酶抑制剂，临床开发用于预防和治疗血栓栓塞性疾病。口服给药后，达比加群酯被迅速吸收并转化为其活性形式达比加群。本研究的目的是在接受维持性血液透析（50 mg）的肾损害（150 mg）或终末期肾病（ESRD）受试者中研究达比加群酯单次口服给药后肾损害对达比加群药代动力学和药效学的影响。
研究方法：这项开放标签、平行组、单中心研究入组了23例轻度、中度或重度肾损害受试者（肌酐清除率分别为> 50至≤ 80、> 30至≤ 50和≤ 30 mL/min）、6例ESRD患者和6例健康受试者。在给药后96小时内采集血液和尿液样本，用于测定达比加群的药代动力学和药效学参数。
结果如下：与健康受试者中的值相比，轻度、中度和重度肾损害受试者中从时间0至无穷大的血浆浓度-时间曲线下面积（AUC ∞）值分别高1.5、3.2和6.3倍。最大血药浓度（Cmax）的变化不大，达到Cmax的时间不变。在重度肾损害受试者中，平均终末消除半衰期加倍（28小时vs对照组14小时）。药效学参数（活化部分凝血活酶时间和埃卡林凝血时间）延长的AUC随着药代动力学变化而增加。在ESRD患者中，剂量标准化AUC ∞约为对照组的两倍。血液透析去除了62 - 68%的剂量。达比加群酯在所有组中均耐受良好。
结论：达比加群暴露量因肾损害而增加，并与肾功能不全的严重程度相关。在这些患者中减少剂量和/或增加给药间隔可能是适当的。在ESRD患者中，达比加群可通过血液透析从血浆中部分清除。
AbstractBackground and Objective: Dabigatran etexilate is an oral direct thrombin inhibitor in clinical development for the prevention and treatment of thromboembolic disorders. Following oral administration, dabigatran etexilate is rapidly absorbed and converted into its active form, dabigatran. The aim of this study was to investigate the effect of renal impairment on the pharmacokinetics and pharmacodynamics of dabigatran following administration of a single oral dose of dabigatran etexilate in subjects with renal impairment (150 mg) or end-stage renal disease (ESRD) on maintenance haemodialysis (50 mg).
Methods: This open-label, parallel-group, single-centre study enrolled 23 subjects with mild, moderate or severe renal impairment (creatinine clearance >50 to ≤80, >30 to ≤50 and ≤30 mL/min, respectively), 6 patients with ESRD and 6 healthy subjects. Blood and urine samples were collected up to 96 hours after dosing for determination of dabigatran pharmacokinetic and pharmacodynamic parameters.
Results: Compared with the values in healthy subjects, the area under the plasma concentration-time curve from time zero to infinity (AUC∞) values were 1.5-, 3.2- and 6.3-fold higher in subjects with mild, moderate and severe renal impairment. Changes in the maximum plasma concentration (Cmax) were modest, and the time to reach the Cmax was unchanged. In subjects with severe renal impairment, the mean terminal elimination half-life was doubled (28 hours vs 14 hours for control). The AUC for prolongation of pharmacodynamic parameters (the activated partial thromboplastin time and ecarin clotting time) increased in line with the pharmacokinetic changes. In patients with ESRD, the dose-normalized AUC∞ was approximately twice the value in the control group. Haemodialysis removed 62–68% of the dose. Dabigatran etexilate was well tolerated in all groups.
Conclusions: Exposure to dabigatran is increased by renal impairment and correlates with the severity of renal dysfunction. A decrease in the dose and/or an increase in the administration interval in these patients may be appropriate. In patients with ESRD, dabigatran can be partly removed from the plasma by haemodialysis.