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Background Concurrent use of dronedarone and oral anti-coagulants are common since both classes of medications are essential to atrial fibrillation (AF) management. Dronedarone is a moderate inhibitor of cytochrome P450 3A4 (CYP3A4) and P-glycoprotein (P-gp). All direct oral anticoagulants (DOACs) are P-gp substrates, and apixaban and rivaroxaban are in addition metabolized by CYP3A4. The current study aims to investigate the impact of dronedarone co-administration on exposure as well as bleeding risk of apixaban or rivaroxaban with physiologically based pharmacokinetic (PBPK) modeling. Method Modeling and simulation were conducted with Simcyp® Simulator. The input parameters required for dronedarone modeling were collected from literature. The developed dronedarone PBPK model was extensively validated with reported DDIs between dronedarone and CYP3A4 and P-gp substrates. After model validation, the model was applied to evaluate DDI potential of dronedarone on exposure and consequent increase in major bleeding risk of apixaban or rivaroxaban in both healthy subjects and AF patients with renal impairment. Result The developed PBPK models accurately describe dronedarone pharmacokinetics following single- oral dose in healthy subjects. The model also predicts DDIs between dronedarone and CYP3A4 and P-gp substrates well, with all fold errors less than 1.5. Co-administration of dronedarone would lead to a 1.23-fold increase and a 1.36-fold increase in AUC24h for rivaroxaban and apixaban in healthy subjects, respectively. In addition, patients with moderate and severe renal impairment co-administered with dronedarone and apixaban would have 1.78-fold and 1.89-fold increase of major bleeding risk, respectively. In contrast, while dronedarone would also increase exposure of rivaroxban in patients with moderate and severe renal impairment, increases in major bleeding risk were 1.18-fold and 1.3-fold, respectively.. Conclusions Dronedarone co-administration would increase major bleeding risks of rivaroxban and apixban. Reduced apixaban dosing regimen of 3.75mg q12h was recommended when dronedarone is co-administered, for AF patients with both normal and impaired renal functions. Reduced rivaroxban dosing regimen of 10mg q24h was recommended when dronedarone is co-administered for AF patients with both moderate and severe impaired renal functions.

BackgroundConcurrent use of dronedarone and oral anti-coagulants are common since both classes of medications are essential to atrial fibrillation management. Dronedarone is a moderate inhibitor of CYP3A4 and P-glycoprotein (P-gp). To date, no drug-drug interaction (DDI) studies between dronedarone and apixaban or rivaroxaban were reported. The current study aims to study the impact of dronedarone co-administration on exposure of apixaban or rivaroxaban with physiologically based pharmacokinetic (PBPK) modeling.MethodModeling and simulation were conducted with Simcyp Simulator. The input parameters required for dronedarone modeling were obtained from literature. The developed dronedarone PBPK model was extensively validated with reported DDIs between dronedarone and CYP3A4 and P-gp substrates. After model validation, the model was applied to evaluate DDI potential of dronedarone on exposure of apixaban or rivaroxaban in both healthy population and patients with renal impairment.ResultThe developed PBPK models accurately describe dronedarone pharmacokinetics following single-dose oral administration in healthy volunteers. The model also predicts DDIs between dronedarone and CYP3A4 and P-gp substrates well, with all fold errors less than 1.5. The AUC of apixaban was increased by 1.36-fold in healthy population due to dronedarone co-administration. In addition, for patients with moderate renal impairment, the AUC of apixaban and rivaroxaban would increase by 1.38-fold and 1.25-fold, respectively.ConclusionsThe established PBPK model of dronedarone was well validated with previously reported DDI studies. Reduced dosing regimens were recommended for patients administered apixaban and dronedarone together. For patients with renal impairment, both dosages of apixaban and rivaroxaban should be adjusted to avoid overexposure when dronedarone is co-administered.