Co-administration of rivaroxaban with drugs that share its elimination pathways: pharmacokinetic effects in healthy subjects

Abstract

Aims: 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).

Methods: The pharmacokinetic effects of substrates or inhibitors of CYP3A4, P-gp and Bcrp (ABCG2) on rivaroxaban were studied in healthy volunteers.

Results: 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%]).

Conclusions: 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.

Keywords: P-glycoprotein; cytochrome P450; drug interactions; healthy subjects; rivaroxaban.

© 2013 Bayer Pharma AG. British Journal of Clinical Pharmacology © 2013 The British Pharmacological Society.

Figures

Figure 1

Plasma concentration–time profile of rivaroxaban (20 mg [fluconazole study] or 10 mg [all other studies] once daily) in the absence and presence of (A) steady-state ketoconazole (400 mg once daily given concomitantly for 5 days), , rivaroxaban alone (n = 20); , rivaroxaban + ketoconazole (n = 20); (B) steady-state ritonavir (600 mg twice daily for 8 days), , rivaroxaban alone (n = 12); , rivaroxaban + ritonavir (n = 12); (C) steady-state clarithromycin (500 mg twice daily for 4 days), , rivaroxaban alone (n = 15); , rivaroxaban + clarithromycin (n = 15); (D) steady-state erythromycin (500 mg three times daily for 5 days), , rivaroxaban alone (n = 15); , rivaroxaban + erythromycin (n = 15); (E) steady-state fluconazole (400 mg once daily for 6 days), , rivaroxaban alone (n = 13); , rivaroxaban + fluconazole (n = 13)

Figure 2

Metabolic clearance and elimination pathways of rivaroxaban based on in vitro investigations [–18] and human studies [12, 13]. All numbers are approximate. aPotentially not absorbed