Application of Static Modeling ­­in the Prediction of In Vivo Drug–Drug Interactions between Rivaroxaban and Antiarrhythmic Agents Based on In Vitro Inhibition Studies

Abstract

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. 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.

Applications of Physiologically Based Pharmacokinetic Modeling of Rivaroxaban—Renal and Hepatic Impairment and Drug‐Drug Interaction Potential

“…A previous physiologically based pharmacokinetic (PBPK) modeling study explored the potential increase in rivaroxaban exposure in patients with renal or hepatic impairment and simultaneous administration of other drugs that inhibit CYP3A4 or P‐gp 17 . More recently, a weak DDI was predicted to exist between rivaroxaban and the antiarrhythmic drugs amiodarone and dronedarone 18 . These antiarrhythmic drugs can be used as part of AF management and may therefore be administered concomitantly with rivaroxaban 19,20 .…”

Impaired Rivaroxaban Clearance in Mild Renal Insufficiency With Verapamil Coadministration: Potential Implications for Bleeding Risk and Dose Selection

“…However the original data supporting these estimates has not been published. Rivaroxaban is reported to be a substrate for efflux transport by P‐glycoprotein (P‐gp) …”

Drug Interactions of New Oral Anticoagulants: Inside and Outside Table Cells

“…Авторы работы, опубликованной в 2017 г., на основании ис-следований in vitro и математического моделирования приходят к заключению, что при совместном приме-нении с амиодароном прирост AUC ривароксабана дол-жен составлять в среднем 37% [12]. Остается не-ясным, какие дозы амиодарона способны вызвать та-кое увеличение, что требует уточнения в фармакоки-нетических исследованиях.…”