Background

Hepatic impairment can impact apixaban pharmacokinetics and pharmacodynamics by decreasing cytochrome P450-mediated metabolism and factor X production.

Objective

This study evaluated the effect of mild or moderate (Child–Pugh A and B) hepatic impairment on apixaban pharmacokinetics, pharmacodynamics, and safety.

Methods

This open-label, parallel-group, single-dose study included eight mildly and eight moderately hepatically impaired subjects, and 16 healthy subjects. Subjects received a single oral apixaban 5-mg dose (day 1). Pharmacokinetic, pharmacodynamic, and safety assessments were completed at prespecified time points. Apixaban maximum plasma concentration and area under the concentration–time curve to infinity were compared between subjects with hepatic impairment and healthy subjects.

Results

Apixaban area under the concentration–time curve to infinity point estimates and 90% confidence intervals were 1.03 (0.80–1.32) and 1.09 (0.85–1.41) for subjects with mild and moderate hepatic impairment vs healthy subjects. Maximum plasma concentration results were similar. Mean (standard deviation) apixaban unbound fraction was 6.8% (1.4), 7.9% (1.8), and 7.1% (1.3) in subjects with mild or moderate hepatic impairment and in healthy subjects. Mean change from baseline in international normalized ratio (3 h post-dose) was 14.7%, 12.7%, and 10.7% for subjects with mild or moderate hepatic impairment and healthy subjects, respectively. A direct relationship was observed between apixaban anti-factor Xa activity and plasma concentration across groups. No serious adverse events or discontinuations due to adverse events occurred.

Conclusions

Mild or moderate hepatic impairment had no clinically relevant impact on apixaban pharmacokinetic or pharmacodynamic measures, suggesting that dose adjustment may not be required.

中文翻译：

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阿哌沙班在轻度或中度肝受损受试者中的药代动力学和药效学

背景

肝功能损害可通过降低细胞色素 P450 介导的代谢和 X 因子产生来影响阿哌沙班的药代动力学和药效学。

客观的

本研究评估了轻度或中度（Child-Pugh A 和 B）肝损伤对阿哌沙班药代动力学、药效学和安全性的影响。

方法

这项开放标签、平行组、单剂量研究包括 8 名轻度和 8 名中度肝受损受试者，以及 16 名健康受试者。受试者接受单次口服阿哌沙班 5 mg 剂量（第 1 天）。在预先指定的时间点完成药代动力学、药效学和安全性评估。在肝功能不全受试者和健康受试者之间比较阿哌沙班最大血浆浓度和浓度-时间曲线下面积至无穷大。

结果

与健康受试者相比，轻度和中度肝损伤受试者与健康受试者的浓度-时间曲线下至无穷大点估计值和 90% 置信区间的面积分别为 1.03 (0.80–1.32) 和 1.09 (0.85–1.41)。最大血浆浓度结果相似。在轻度或中度肝损伤受试者和健康受试者中，平均（标准差）阿哌沙班未结合分数为 6.8% (1.4)、7.9% (1.8) 和 7.1% (1.3)。对于轻度或中度肝功能不全的受试者和健康受试者，国际标准化比率（给药后 3 小时）与基线的平均变化分别为 14.7%、12.7% 和 10.7%。观察到阿哌沙班抗 Xa 因子活性与各组血浆浓度之间存在直接关系。未发生严重不良事件或因不良事件而停药。

结论

轻度或中度肝功能损害对阿哌沙班药代动力学或药效学测量没有临床相关影响，表明可能不需要调整剂量。