Perpetrator effects of ciclosporin (P-glycoprotein inhibitor) and its combination with fluconazole (CYP3A inhibitor) on the pharmacokinetics of rivaroxaban in healthy volunteers
Perpetrator effects of ciclosporin (P-glycoprotein inhibitor) and its combination with fluconazole (CYP3A inhibitor) on the pharmacokinetics of rivaroxaban in healthy volunteers
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DOI：
10.1111/bcp.13934
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发表时间：
2019-07-01
影响因子：
3.4
通讯作者：
Czock, David
中科院分区：
文献类型：
--
作者：
Brings, Antonia;Lehmann, Marie-Louise;Czock, David
目的联合p糖蛋白（P-gp）和强细胞色素P450 (CYP) 3A抑制剂（如酮康唑）的药物可显著增加利伐沙班暴露。本研究的目的是探讨强效P-gp抑制剂环孢素及其与中度CYP3A抑制剂氟康唑联合使用对利伐沙班药代动力学和CYP3A活性的影响。方法12名健康志愿者分别口服利伐沙班20 mg、联合环孢素（剂量个个化口服方案）、联合环孢素和氟康唑（400 mg / d）口服。使用咪达唑仑微剂量估计CYP3A4活性。采用非区室法和区室法分析药代动力学。结果与基线相比，环孢素使利伐沙班平均暴露量增加47%(90%置信区间28-68%)，最大浓度增加104% (70-146%)，CYP3A4活性降低34%（25-42%）。环孢素联合氟康唑使利伐沙班的平均暴露量增加了86%(58-119%)，最大浓度增加了115%(83-153%)，明显高于单独使用利伐沙班和氟康唑的历史对照组，并使CYP3A4活性降低了79%（76-82%）。结论利伐沙班联合多种消除途径单一调节剂或多种单一消除途径调节剂（CYP3A、P-gp）治疗患者需特别小心。
Aims Rivaroxaban exposure is considerably increased by drugs that are combined P-glycoprotein (P-gp) and strong cytochrome P450 (CYP) 3A inhibitors (e.g. ketoconazole). The aim of the present study was to investigate the effects of the potent P-gp inhibitor ciclosporin and its combination with the moderate CYP3A inhibitor fluconazole on rivaroxaban pharmacokinetics and on CYP3A activity. Methods Twelve healthy volunteers received 20 mg rivaroxaban orally alone, in combination with ciclosporin (dose-individualized oral regimen), and in combination with ciclosporin and fluconazole (400 mg day(-1) orally). CYP3A4 activity was estimated using a midazolam microdose. Pharmacokinetics was analysed using noncompartmental and compartmental methods. Results Compared to baseline, ciclosporin increased rivaroxaban average exposure by 47% (90% confidence interval 28-68%), maximum concentration by 104% (70-146%), and decreased CYP3A4 activity by 34% (25-42%). Ciclosporin combined with fluconazole increased rivaroxaban average exposure by 86% (58-119%) and maximum concentration by 115% (83-153%), which was considerably stronger than observed in historical controls receiving rivaroxaban with fluconazole alone, and decreased CYP3A4 activity by 79% (76-82%). Conclusion Patients treated with rivaroxaban in combination with single modulators of multiple elimination pathways or multiple modulators of single elimination pathways (CYP3A, P-gp) require particular care.