Clin Res Cardiol 106, Suppl 2, October 2017

Combination of dronedarone and rivaroxaban – new insights into pharmacokinetics from a physiological-based pharmakokinetic (PBPK) model

B. Hügl1, S. Willmann2, S. Kraff3, M. Henry4, M. Mundhenke5

1Klinik für Kardiologie/Rhythmologie, Marienhaus Klinikum St. Elisabeth Neuwied, Neuwied; 2Clinical Pharmacometrics, Bayer AG, Wuppertal; 3Clinical PK Cardiovascular, Bayer AG, Wuppertal; 4Global Medical Affairs, Bayer AG, Berlin; 5Medical Affairs Therapeutic Area Cardiovascular, Bayer Vital GmbH, Leverkusen;

Introduction: Rhythm control plus anticoagulation in patients with atrial fibrillation is often clinically indicated. In structural heart disease amiodarone or dronedarone are guideline recommended substances for rhythm control. Both, amiodarone and dronedarone, act as CYP3A4/5 and P-gp inhibitors. In combinations with NOACs, dronedarone is  contraindicated in dabigatran use. The apixaban label does not explicitly mention the combination with dronedarone and for edoxaban the dosage needs to be halfed because of edoxabans major P-gp metabolism pathway. Dronedarone/rivaroxaban combination was allowed to be used in the randomized controlled trials for rivaroxaban in ROCKET-AF, X-Vert  and VENTURE-AF.   However, the label of rivaroxaban states in the section ’Interaction with other medicinal products’  that dronedarone should not be used concomitantly because of limited clinical data. Here we describe new insights into drug-drug interactions of dronedarone/rivaroxaban using PBPK modelling. Methods: Clinical development of rivaroxaban has been supported by physiologically-based pharmacokinetic (PBPK) modelling. PBPK modelling is a widely used technique in pharmaceutical R&D and academia that aims to describe absorption, distribution, metabolisation and excretion of a drug on the basis of prior physiological knowledge. A previously developed PBPK model for rivaroxaban in adults was used to simulate the influence of combined CYP3A4/5 and P-gp inhibition on rivaroxaban exposure. Results: Table 1 shows the predicted factor of AUC  (Area under Curve) increase for rivaroxaban in combination of differing levels of CYP3A4/5 and P-gp inhibition in the PBPK model. *Factors of AUC increase for rivaroxaban in combination with amiodarone as a weak CYP3A4/5 inhibitor without exactly known P-gp inhibition level ** Factors of AUC increase for rivaroxaban in combination with dronedarone as moderate CYP3A4/5 inhibitor without exactly known P-gp inhibition level § Based on FDA criteria (using midazolam as sensitive index substrate) The AUC after single dose administration of 20 mg rivaroxaban tablets was in the range of approximately 1500 to 3000 µg·h/L in healthy volunteers Conclusion: In line with other data emerging (Cheong et al. 2017) the PBPK model presented predicts a weak to moderate increase of AUC dronedarone/rivaroxaban combination for rivaroxaban in healthy adults. For clinical decision making other individual factors, most importantly renal insufficiency and risk factors for bleeding, seems to be more crucial for responsible use of dronedarone/rivaroxaban combination. Simulated PBPK data for rivaroxaban supports the decision to give dronedarone/rivaroxaban combination no contraindication or special warning in the label for stroke prophylaxis in non-valvular atrial fibrillation.

http://www.abstractserver.de/dgk2017/ht/abstracts//P204.htm