Clinical significance of the rivaroxaban–dronedarone interaction: insights from physiologically based pharmacokinetic modelling

Patients with atrial fibrillation may require rhythm control therapy in addition to anticoagulation therapy for the prevention of stroke. Since 2012, the European Society of Cardiology and European Heart Rhythm Association guidelines have recommended non-vitamin K antagonist oral anticoagulants, including rivaroxaban, for the prevention of stroke in patients with atrial fibrillation. During the same period, these guidelines have also recommended dronedarone or amiodarone as second-line rhythm control agents in certain patients with atrial fibrillation and no contraindications. Amiodarone and dronedarone both strongly inhibit P-glycoprotein, while dronedarone is a moderate and amiodarone a weak inhibitor of cytochrome P450 3A4 (CYP3A4). Based on these data and evidence from physiologically based pharmacokinetic modelling, amiodarone and dronedarone are expected to have similar effects on rivaroxaban exposure resulting from P-glycoprotein and CYP3A4 inhibition. However, the rivaroxaban label recommends against the concomitant use of dronedarone, but not amiodarone, citing a lack of evidence on the concomitant use of rivaroxaban and dronedarone as the reason for the different recommendations. In this report, we discuss evidence from clinical studies and physiologically based pharmacokinetic modelling on the potential for increased rivaroxaban exposure resulting from drug–drug interaction between rivaroxaban and dronedarone or amiodarone. The current evidence supports the same clinical status and concomitant use of either amiodarone or dronedarone with rivaroxaban, which could be considered in future recommendations.