A 2023 review delved into the clinical significance of the interaction between rivaroxaban and dronedarone, utilizing insights from physiologically based pharmacokinetic (PBPK) modeling. The study explored the potential for increased rivaroxaban exposure arising from drug-drug interactions with either dronedarone or amiodarone, both of which are used alongside anticoagulation in rhythm control therapy for patients with atrial fibrillation (AF). Despite existing guidelines suggesting caution with the concomitant use of rivaroxaban and dronedarone due to limited clinical evidence, the review provided critical analysis from both clinical studies and PBPK modeling to argue for an adjustment in these recommendations. The study highlighted that both amiodarone and dronedarone inhibit P-glycoprotein significantly, while amiodarone is a weak inhibitor and dronedarone is a moderate inhibitor of CYP3A4. The PBPK modeling forecasted similar increases in rivaroxaban exposure when combined with either antiarrhythmic, with predicted increases in the area under the curve (AUC) of 1.58-fold for amiodarone and up to 1.82-fold for dronedarone. Importantly, this increased exposure was deemed unlikely to be clinically significant in patients without renal impairment, suggesting that the interaction may not substantially elevate bleeding risk compared to the standalone use of rivaroxaban. The paper advocated for the reevaluation of current clinical guidelines, proposing that the concomitant use of dronedarone and rivaroxaban could assume the same clinical status as the use of amiodarone with rivaroxaban. [1]
A 2022 review explored the effects of concurrent administration of dronedarone with apixaban and rivaroxaban using physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) modeling. The study utilized the Simcyp® Simulator to construct a PBPK model for dronedarone, incorporating literature-derived parameters. The model was validated against existing data on drug-drug interactions involving CYP3A4 and P-glycoprotein substrates. The central objective was to evaluate changes in exposure and associated bleeding risks when apixaban (5 mg every 12 hours) or rivaroxaban (20 mg every 24 hours) were co-administered with dronedarone in aged or renally impaired cohorts. Outcomes indicated that dronedarone co-administration resulted in a modest increase in the area under the concentration-time curve for both rivaroxaban and apixaban, leading to enhanced exposure and elevated bleeding risk. Specifically, rivaroxaban exposure increased by 1.29 to 1.31-fold, and apixaban by 1.33 to 1.46-fold. The physiological modeling further predicted that major bleeding risks were likely potentiated for apixaban with a potential increase in risk up to 1.95-fold, while rivaroxaban saw less than a 1.5-fold increase in bleeding risk in patients with normal or compromised renal function. This modeling led to the recommendation of reduced dosing regimens for apixaban and rivaroxaban when administered alongside dronedarone in atrial fibrillation patients, suggesting adjustments to maintain therapeutic efficacy while mitigating bleeding risk. [2]
A 2022 abstract study used a physiologically based pharmacokinetic model to assess the drug interaction between dronedarone and the anticoagulants apixaban and rivaroxaban. The analysis found that co-administration with dronedarone led to a modest increase in drug exposure for both anticoagulants, resulting in an elevated risk of major bleeding. Specifically, apixaban exposure increased by 1.33 to 1.46-fold, correlating with a potential near-doubling of bleeding risk, while rivaroxaban exposure and bleeding risk increased to a lesser degree. Consequently, the study recommended reducing the dosage of both apixaban and rivaroxaban when they are used concurrently with dronedarone in atrial fibrillation patients to preserve therapeutic benefits while minimizing the heightened bleeding danger. [3]