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

• Verfasst von: Brings, Antonia [VerfasserIn]
• Verfasst von: Lehmann, Marie-Louise [VerfasserIn]
• Verfasst von: Foerster, Kathrin [VerfasserIn]
• Verfasst von: Burhenne, Jürgen [VerfasserIn]
• Verfasst von: Weiß, Johanna [VerfasserIn]
• Verfasst von: Haefeli, Walter E. [VerfasserIn]
• Verfasst von: Czock, David [VerfasserIn]
• Titel: Perpetrator effects of ciclosporin (P-glycoprotein inhibitor) and its combination with fluconazole (CYP3A inhibitor) on the pharmacokinetics of rivaroxaban in healthy volunteers
• Verf.angabe: Antonia Brings, Marie-Louise Lehmann, Kathrin I. Foerster, Jürgen Burhenne, Johanna Weiss, Walter E. Haefeli, David Czock
• E-Jahr: 2019
• Jahr: 25 March 2019
• Umfang: 10 S.
• Fussnoten: Gesehen am 25.07.2019
• Titel Quelle: Enthalten in: British journal of clinical pharmacology
• Ort Quelle: Oxford : Wiley-Blackwell, 1974
• Jahr Quelle: 2019
• Band/Heft Quelle: 85(2019), 7, Seite 1528-1537
• ISSN Quelle: 1365-2125
• DOI: doi:10.1111/bcp.13934
• Datenträger: Online-Ressource
• Sprache: eng
• Sach-SW: ciclosporin
• Sach-SW: cytochrome P450 CYP3A
• Sach-SW: drug-drug interaction
• Sach-SW: fluconazole
• Sach-SW: midazolam
• Sach-SW: pharmacokinetics
• Sach-SW: rivaroxaban
• K10plus-PPN: 1670054845

Abstract

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.