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

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...

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Main Authors: Brings, Antonia (Author) , Lehmann, Marie-Louise (Author) , Foerster, Kathrin (Author) , Burhenne, Jürgen (Author) , Weiß, Johanna (Author) , Haefeli, Walter E. (Author) , Czock, David (Author)
Format: Article (Journal)
Language:English
Published: 25 March 2019
In: British journal of clinical pharmacology
Year: 2019, Volume: 85, Issue: 7, Pages: 1528-1537
ISSN:1365-2125
DOI:10.1111/bcp.13934
Online Access:Verlag, Volltext: http://dx.doi.org/10.1111/bcp.13934
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Author Notes:Antonia Brings, Marie-Louise Lehmann, Kathrin I. Foerster, Jürgen Burhenne, Johanna Weiss, Walter E. Haefeli, David Czock
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Summary: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.
Item Description:Gesehen am 25.07.2019
Physical Description:Online Resource
ISSN:1365-2125
DOI:10.1111/bcp.13934

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