Predictors of dronedarone plasma drug concentrations and effect on atrial fibrillation/atrial flutter recurrence: Analyses from the EURIDIS and ADONIS studies

Abstract

Background: In this post hoc analysis, we assessed patient characteristics as predictors of dronedarone trough concentrations and characterized the relationship of trough concentrations of dronedarone with its efficacy and safety. Hypothesis: Dronedarone is recommended as a 400 mg twice daily dose taken orally with meals. We hypothesize that drug concentration/bioavailability of dronedarone, measured as above- and below-median trough concentrations, does not impact the efficacy outcomes. Methods: Average trough concentrations (Ctrough_avg) across multiple timepoints were calculated for each patient, and patient Ctrough_avg values were categorized as below-median or above-median concentrations. The effect of patient baseline characteristics on dronedarone Ctrough_avg was assessed in the below-median versus above-median groups. The effect of dronedarone in each Ctrough_avg group versus placebo on risk of first atrial fibrillation/atrial flutter (AF/AFL) recurrence and safety was also evaluated. Results: Overall, 1795 plasma samples were available from 507 dronedarone-treated patients. An above-median Ctrough_avg was associated with age ≥75 years, female sex, lower weight, higher pacemaker use, and higher oral anticoagulant use. The risk of adjudicated first AF/AFL recurrence was significantly lower with dronedarone versus placebo in the below-median (hazard ratio [HR]: 0.71; 95% confidence interval [CI]: 0.56–0.91; p =.0054) and above-median groups (HR: 0.63; 95% CI: 0.50–0.81; p =.0002). No difference in risk of AF/AFL recurrence was observed between the above- and below-median groups. Safety and tolerability of dronedarone were similar between groups. Conclusion: Significant reduction in AF/AFL recurrence was observed in patients treated with dronedarone versus placebo, regardless of dronedarone concentrations above or below the median value.