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

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.