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: | , , , , , , |
|---|---|
| Format: | Article (Journal) |
| Language: | English |
| Published: |
25 March 2019
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| 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 |
MARC
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| 245 | 1 | 0 | |a Perpetrator effects of ciclosporin (P-glycoprotein inhibitor) and its combination with fluconazole (CYP3A inhibitor) on the pharmacokinetics of rivaroxaban in healthy volunteers |c Antonia Brings, Marie-Louise Lehmann, Kathrin I. Foerster, Jürgen Burhenne, Johanna Weiss, Walter E. Haefeli, David Czock |
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| 520 | |a 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. | ||
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