Rivaroxaban, a direct Factor Xa inhibitor, is indicated for stroke prevention in non-valvular atrial fibrillation (AF). Studies have revealed that the clearance of rivaroxaban is largely attributed to CYP3A4, CYP2J2 metabolism and P-gp efflux pathways. Amiodarone and dronedarone are anti-arrhythmic agents employed in AF management. Amiodarone, dronedarone and their major metabolites, N-desethylamiodarone (NDEA) and N-desbutyldronedarone (NDBD) demonstrate inhibitory effects on CYP3A4 and CYP2J2 with FDA recommended probe substrates. Additionally, both amiodarone and dronedarone are known P-gp inhibitors. Hence, the concomitant administration of these anti-arrhythmic agents has the potential to augment the systemic exposure of rivaroxaban through simultaneous impairment of its clearance pathways. Currently, however, there is a lack of clinical data on the extent of these postulated DDIs. In this study, in vitro inhibition assays using rivaroxaban as the probe substrate demonstrated that both dronedarone and NDBD produced reversible inhibition as well as irreversible mechanism-based inactivation (MBI) of CYP3A4- and CYP2J2-mediated metabolism of rivaroxaban. However, amiodarone and NDEA were observed to cause reversible inhibition as well as MBI of CYP3A4 but not CYP2J2. Additionally, amiodarone, NDEA and dronedarone but not NDBD were determined to inhibit P-gp mediated rivaroxaban transport. The in vitro inhibition parameters were fitted into a mechanistic static model which predicted a 37% and 31% increase in rivaroxaban exposure due to the inhibition of hepatic and gut metabolism by amiodarone and dronedarone respectively. A separate model quantifying the inhibition of P-gp mediated efflux by amiodarone or dronedarone projected a 9% increase in rivaroxaban exposure.
- cytochrome P450
- drug-drug interactions
- efflux transporters (P-gp, BCRP, MRP, MATE, BSEP, etc)
- enzyme inactivation/mechanism-based inhibition
- enzyme inhibitors
- in vitro-in vivo prediction (IVIVE)
- The American Society for Pharmacology and Experimental Therapeutics