Effects of renal impairment on the pharmacokinetics, pharmacodynamics and safety of rivaroxaban, an oral, direct Factor Xa inhibitor
Effects of renal impairment on the pharmacokinetics, pharmacodynamics and safety of rivaroxaban, an oral, direct Factor Xa inhibitor
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DOI：
10.1111/j.1365-2125.2010.03753.x
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发表时间：
2010-11-01
影响因子：
3.4
通讯作者：
Bruck, Heike
中科院分区：
文献类型：
--
作者：
Kubitza, Dagmar;Becka, Michael;Bruck, Heike
在本研究开始之前，已经知道利伐沙班是部分通过肾脏清除的，并且预计肾功能不全对利伐沙班药代动力学和暴露的影响。由于许多利伐沙班的目标适应症患者将是老年人，因此必须精确定量地了解肾功能对利伐沙班药代动力学和暴露的影响，以获得足够的标签推荐（在III期研究提供的获益/风险背景下）来指导治疗。这项研究提供了利伐沙班药代动力学和药效学行为在肾功能损害包括严重肾功能损害受试者的详细见解。本研究评估了肾功能受损对口服直接Xa因子抑制剂利伐沙班（10mg单剂量）的药代动力学、药效学和安全性的影响。方法根据测定的肌酐清除率对32名受试者进行分层：健康对照组（>= 80 ml min-1）、轻度组（50-79 ml min-1）、中度组（30-49 ml min-1）和重度组（< 30 ml min-1）。结果随着肾功能损害的加重，利伐沙班的肾清除率降低。因此，血浆浓度升高，血浆浓度-时间曲线下面积（AUC） ls -平均值比健康对照组高1.44倍（90%置信区间[CI] 1.1, 1.9；轻度），1.52倍（90% CI 1.2, 2.0；中度）和1.64倍（90% CI 1.2, 2.2；重度损伤）。凝血酶原时间延长的ls -平均值分别比健康受试者高1.33倍（90% CI 0.92, 1.92；轻度）、2.16倍（90% CI 1.51, 3.10中度）和2.44倍（90% CI 1.70, 3.49重度）。同样，轻度肾功能损害受试者的Xa因子抑制的ls平均AUC比健康受试者高1.50倍（90% CI 1.07, 2.10）。在中度和重度肾损害受试者中，分别比健康受试者高1.86倍（90% CI 1.34, 2.59）和2.0倍（90% CI 1.44, 2.78）。结论利伐沙班清除率随着肾脏损害的加重而降低，导致血浆暴露量增加和药效学效应增加，这与部分肾脏排泄药物的预期一致。然而，肾功能对利伐沙班清除率的影响是中等的，即使在严重肾功能损害的受试者中也是如此。
center dot Prior to the commencement of this study, it was already known that rivaroxaban is partially cleared via the kidneys and an influence of renal insufficiency on rivaroxaban pharmacokinetics and exposure was anticipated.WHAT THIS STUDY ADDScenter dot As many patients in the target indications of rivaroxaban will be elderly, a precise quantitative knowledge of the influence of renal function on rivaroxaban pharmacokinetics and exposure is mandatory for adequate labelling recommendations (in the context of benefit/risk provided by phase III studies) to guide therapy. This study provided detailed insight on both rivaroxaban pharmacokinetics and pharmacodynamic behaviour in renal impairment including severely renally impaired subjects.AIMThis study evaluated the effects of impaired renal function on the pharmacokinetics, pharmacodynamics and safety of rivaroxaban (10 mg single dose), an oral, direct Factor Xa inhibitor.METHODSSubjects (n = 32) were stratified based on measured creatinine clearance: healthy controls (>= 80 ml min-1), mild (50-79 ml min-1), moderate (30-49 ml min-1) and severe impairment (< 30 ml min-1).RESULTSRenal clearance of rivaroxaban decreased with increasing renal impairment. Thus, plasma concentrations increased and area under the plasma concentration-time curve (AUC) LS-mean values were 1.44-fold (90% confidence interval [CI] 1.1, 1.9; mild), 1.52-fold (90% CI 1.2, 2.0; moderate) and 1.64-fold (90% CI 1.2, 2.2; severe impairment) higher than in healthy controls. Corresponding values for the LS-mean of the AUC for prolongation of prothrombin time were 1.33-fold (90% CI 0.92, 1.92; mild), 2.16-fold (90% CI 1.51, 3.10 moderate) and 2.44-fold (90% CI 1.70, 3.49 severe) higher than in healthy subjects, respectively. Likewise, the LS-mean of the AUC for Factor Xa inhibition in subjects with mild renal impairment was 1.50-fold (90% CI 1.07, 2.10) higher than in healthy subjects. In subjects with moderate and severe renal impairment, the increase was 1.86-fold (90% CI 1.34, 2.59) and 2.0-fold (90% CI 1.44, 2.78) higher than in healthy subjects, respectively.CONCLUSIONSRivaroxaban clearance is decreased with increasing renal impairment, leading to increased plasma exposure and pharmacodynamic effects, as expected for a partially renally excreted drug. However, the influence of renal function on rivaroxaban clearance was moderate, even in subjects with severe renal impairment.