Co-administration of rivaroxaban with drugs that share its elimination pathways: pharmacokinetic effects in healthy subjects
Article first published online: 20 AUG 2013
© 2013 Bayer Pharma AG. British Journal of Clinical Pharmacology © 2013 The British Pharmacological Society
British Journal of Clinical Pharmacology
Special Issue: Cancer Therapeutics Themed Section
Volume 76, Issue 3, pages 455–466, September 2013
How to Cite
Mueck, W., Kubitza, D. and Becka, M. (2013), Co-administration of rivaroxaban with drugs that share its elimination pathways: pharmacokinetic effects in healthy subjects. British Journal of Clinical Pharmacology, 76: 455–466. doi: 10.1111/bcp.12075
- Issue published online: 20 AUG 2013
- Article first published online: 20 AUG 2013
- Accepted manuscript online: 11 JAN 2013 06:34AM EST
- Manuscript Accepted: 24 DEC 2012
- Manuscript Received: 5 SEP 2012
- Bayer HealthCare Pharmaceuticals
- Janssen Research & Development, LLC
- cytochrome P450;
- drug interactions;
- healthy subjects;
The anticoagulant rivaroxaban is an oral, direct Factor Xa inhibitor for the management of thromboembolic disorders. Metabolism and excretion involve cytochrome P450 3A4 (CYP3A4) and 2J2 (CYP2J2), CYP-independent mechanisms, and P-glycoprotein (P-gp) and breast cancer resistance protein (Bcrp) (ABCG2).
The pharmacokinetic effects of substrates or inhibitors of CYP3A4, P-gp and Bcrp (ABCG2) on rivaroxaban were studied in healthy volunteers.
Rivaroxaban did not interact with midazolam (CYP3A4 probe substrate). Exposure to rivaroxaban when co-administered with midazolam was slightly decreased by 11% (95% confidence interval [CI] −28%, 7%) compared with rivaroxaban alone. The following drugs moderately affected rivaroxaban exposure, but not to a clinically relevant extent: erythromycin (moderate CYP3A4/P-gp inhibitor; 34% increase [95% CI 23%, 46%]), clarithromycin (strong CYP3A4/moderate P-gp inhibitor; 54% increase [95% CI 44%, 64%]) and fluconazole (moderate CYP3A4, possible Bcrp [ABCG2] inhibitor; 42% increase [95% CI 29%, 56%]). A significant increase in rivaroxaban exposure was demonstrated with the strong CYP3A4, P-gp/Bcrp (ABCG2) inhibitors (and potential CYP2J2 inhibitors) ketoconazole (158% increase [95% CI 136%, 182%] for a 400 mg once daily dose) and ritonavir (153% increase [95% CI 134%, 174%]).
Results suggest that rivaroxaban may be co-administered with CYP3A4 and/or P-gp substrates/moderate inhibitors, but not with strong combined CYP3A4, P-gp and Bcrp (ABCG2) inhibitors (mainly comprising azole-antimycotics, apart from fluconazole, and HIV protease inhibitors), which are multi-pathway inhibitors of rivaroxaban clearance and elimination.