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 F actor X a 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 (B crp) (ABCG2). Methods: The pharmacokinetic effects of substrates or inhibitors of CYP3A4,P‐gp and B crp (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 B crp [ABCG2] inhibitor; 42% increase [95%CI 29%, 56%]). A significant increase in rivaroxaban exposure was demonstrated with the strong CYP3A4,P‐gp/B crp (ABCG 2) 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 B crp (ABCG2) inhibitors (mainly comprising azole‐antimycotics, apart from fluconazole, and HIV protease inhibitors), which are multi‐pathway inhibitors of rivaroxaban clearance and elimination.