Clinical Pharmacology and Toxicology, Department of General Internal Medicine, Inselspital, Bern University Hospital, University of Bern, Switzerland.
Institute of Pharmacology, University of Bern, Switzerland.
Br J Clin Pharmacol. 2021 Mar;87(3):1466-1474. doi: 10.1111/bcp.14553. Epub 2020 Oct 25.
To investigate the influence of a cytochrome P450 CYP3A4 and efflux transporter P-glycoprotein (P-gp) inducing Hypericum perforatum extract on the pharmacokinetics and pharmacodynamics of rivaroxaban.
Open-label, nonrandomized, sequential treatment interaction study. Following CYP3A4 and P-gp phenotyping using low-dose midazolam and fexofenadine, 12 healthy volunteers received a single oral dose of 20 mg rivaroxaban and rivaroxaban plasma concentrations and inhibition of the activated coagulation factor X (factor Xa) activity were measured prior to and up to 48 h postdosing. The procedures were repeated after 2 weeks' treatment with the H. perforatum extract.
The geometric mean ratios for the area under the concentration-time curve and C of rivaroxaban after/before induction with the H. perforatum extract were 0.76 (90% confidence interval [CI] 0.70, 0.82) and 0.86 (90% CI 0.76, 0.97), respectively. Inhibition of factor Xa activity was reduced with a geometric mean area under the effect-time curve ratio after/before induction of 0.80 (90% CI 0.71, 0.89). No clinically significant differences were found regarding T (median 1.5 vs 1 h, P = .26) and terminal elimination half-life (mean 10.6 vs 10.8 h, P = .93) of rivaroxaban. The H. perforatum extract significantly induced CYP3A4 and P-gp activity, as evidenced by phenotyping.
The CYP3A4/P-gp inducing H. perforatum extract caused a decrease of rivaroxaban exposure with a proportional decrease of the pharmacodynamic effect. Although the data do not justify a contraindication for the combination or a systematic adjustment of rivaroxaban dosage, avoidance of the combination or laboratory monitoring should be considered in patients taking hyperforin-containing H. perforatum extracts with rivaroxaban.
研究细胞色素 P450 CYP3A4 和外排转运蛋白 P-糖蛋白（P-gp）诱导贯叶连翘提取物对利伐沙班药代动力学和药效学的影响。
采用低剂量咪达唑仑和非索非那定进行 CYP3A4 和 P-gp 表型分析后，进行开放标签、非随机、序贯治疗相互作用研究。12 名健康志愿者单次口服 20mg 利伐沙班，在给药前和给药后 48 小时内测量利伐沙班血浆浓度和激活凝血因子 X（因子 Xa）活性的抑制作用。在 2 周贯叶连翘提取物治疗后重复这些程序。
贯叶连翘提取物诱导后/诱导前利伐沙班的 AUC 和 C 的几何均数比值分别为 0.76（90%置信区间[CI] 0.70，0.82）和 0.86（90%CI 0.76，0.97）。因子 Xa 活性抑制作用降低，诱导后/诱导前效应时间曲线下面积的几何均数比值为 0.80（90%CI 0.71，0.89）。利伐沙班的 T（中位数 1.5 比 1 小时，P =.26）和终末消除半衰期（平均 10.6 比 10.8 小时，P =.93）无临床显著差异。贯叶连翘提取物显著诱导 CYP3A4 和 P-gp 活性，表型分析证实了这一点。
CYP3A4/P-gp 诱导的贯叶连翘提取物导致利伐沙班暴露减少，药效作用成比例减少。尽管数据不支持该组合的禁忌或系统调整利伐沙班剂量，但在服用含有贯叶连翘提取物的患者中，应考虑避免联合用药或实验室监测与利伐沙班联合使用。
