What is it about?
Rivaroxaban, a direct Factor Xa inhibitor, is indicated for stroke prevention in nonvalvular atrial fibrillation (AF). Studies have revealed that the clearance of rivaroxaban is largely attributed to CYP3A4, CYP2J2 metabolism, and P-glycoprotein (P-gp) efflux pathways. Amiodarone and dronedarone are antiarrhythmic 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 U.S. Food and Drug Administration–recommended probe substrates. In addition, both amiodarone and dronedarone are known P-gp inhibitors. Hence, the concomitant administration of these antiarrhythmic agents has the potential to augment the systemic exposure of rivaroxaban through simultaneous impairment of its clearance pathways. Currently, however, clinical data on the extent of these postulated drug–drug interactions are lacking.
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Why is it important?
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 of CYP3A4- and CYP2J2-mediated metabolism of rivaroxaban. However, amiodarone and NDEA were observed to cause reversible inhibition as well as mechanism-based inactivation of CYP3A4 but not CYP2J2. In addition, 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.
Perspectives
Amiodarone, dronedarone, NDEA, and NDBD cause reversible inhibition and irreversible MBI of CYP3A4 with rivaroxaban as the probe substrate. Amiodarone and NDEA, unlike dronedarone and NDBD, do not inhibit CYP2J2. Amiodarone, dronedarone, and NDEA, but not NDBD, inhibit P-gp–mediated efflux of rivaroxaban. Static modeling predicted a weak DDI risk between rivaroxaban and amiodarone or dronedarone. Fundamental limitations of the static model implied that molecular interactions between rivaroxaban and the antiarrhythmic agents and their metabolites via CYP3A4, CYP2J2, and P-gp were not considered in entirety. Future work would involve the assimilation of these in vitro inhibition parameters into a dynamic PBPK model, from which a more accurate quantitation of DDI magnitude can be derived.
Dr Eric Chun Yong Chan
National University of Singapore
Read the Original
This page is a summary of: Application of Static Modeling in the Prediction of In Vivo Drug–Drug Interactions between Rivaroxaban and Antiarrhythmic Agents Based on In Vitro Inhibition Studies, Drug Metabolism and Disposition, January 2017, American Society for Pharmacology & Experimental Therapeutics (ASPET),
DOI: 10.1124/dmd.116.073890.
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