Does co-administration of rivaroxaban with CYP3A4, P-gp, and Bcrp inhibitors alter rivaroxaban exposure in healthy volunteers?
Rivaroxaban should not be co-administered with strong combined CYP3A4, P-gp, and Bcrp inhibitors like ketoconazole and ritonavir due to significant increases in drug exposure.
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.
Mueck et al. (2013) studied this question.