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

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 (C-trough_avg) across multiple timepoints were calculated for each patient, and patient C-trough_avg values were categorized as below-median or above-median concentrations. The effect of patient baseline characteristics on dronedarone C-trough_avg was assessed in the below-median versus above-median groups. The effect of dronedarone in each C-trough_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 C-trough_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.