Effects of <scp><i>Hypericum perforatum</i></scp> (St John's wort) on the pharmacokinetics and pharmacodynamics of rivaroxaban in humans

Abstract

Aims 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. Methods 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. Results The geometric mean ratios for the area under the concentration–time curve and C max 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 max (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. Conclusion 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.

Topics & Concepts