Perpetrator effects of ciclosporin (P-glycoprotein inhibitor) and its combination with fluconazole (CYP3A inhibitor) on the pharmacokinetics of rivaroxaban in healthy volunteers.

Antonia Brings, Marie-Louise Lehmann, Kathrin I Foerster, Jürgen Burhenne, Johanna Weiss, Walter E Haefeli, David Czock

British journal of clinical pharmacology 2019 Jul

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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. 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. 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%). 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. © 2019 The British Pharmacological Society.

Citation

Antonia Brings, Marie-Louise Lehmann, Kathrin I Foerster, Jürgen Burhenne, Johanna Weiss, Walter E Haefeli, David Czock. Perpetrator effects of ciclosporin (P-glycoprotein inhibitor) and its combination with fluconazole (CYP3A inhibitor) on the pharmacokinetics of rivaroxaban in healthy volunteers. British journal of clinical pharmacology. 2019 Jul;85(7):1528-1537