Abstract 9650: Enhanced Efficiency of Atrial Fibrillation Conversion to Sinus Rhythm by Inhaled Flecainide HPbCD Formulation Revealed by Concentration-time Area Analysis

• Published in: Circulation (New York, N.Y.) N.Y.), 2019-11, Vol.140 (Suppl_1 Suppl 1), p.A9650-A9650
• Main Authors: C. Pedreira, Giovanna, A. Medeiros, Sofia, Tessarolo Silva, Fernanda, Bortolotto, Alexandre, Araujo Silva, Bruna, Marum, Alexandre, Nearing, Bruce, Madhavapeddi, Prashanti, Hurrey, Michael, Schuler, Carlos, Belardinelli, Luiz, Verrier, Richard
• Format: Article
• Language: English
• ISSN: 0009-7322; 1524-4539
• DOI: 10.1161/circ.140.suppl_1.9650

IntroductionConversion of atrial fibrillation (AF) to normal sinus rhythm (NSR) requires rapid, optimally dosed delivery of the antiarrhythmic agent. A handheld breath-activated nebulizer has been used to deliver flecainide via oral inhalation in the clinic; however, the optimal formulation has not been determined.HypothesisUse of solubility-enhancing cyclodextrin excipient in the formulation will enhance the efficiency of flecainide to convert AF to NSR.MethodsIn 11 anesthetized Yorkshire pigs, intrapericardial injection of acetylcholine followed by burst pacing was used to induce AF reproducibly. We compared historical data from animals given a traditional flecainide acetate formulation (N=6) with data obtained in 5 pigs given a novel preparation of flecainide acetate using cyclodextrin as the excipient (flecainide HPβCD) to increase aqueous solubility of the drug. Both solutions were instilled intratracheally at 2 min following AF initiation. The pharmacokinetic parameter measured was the concentration-time area (AUC) from time 0 (drug instillation) to time of AF conversion.ResultsThe HPβCD and acetate solutions of flecainide converted AF to NSR in all animals at 2.5±0.4 and 5.7±1.3 min (p=0.05, mean ± SEM), respectively. The AUC at the time of conversion following intratracheal instillation of flecainide HPβCD (1.0 mg/kg) was 1,759±382 ng/ml/min and of flecainide acetate (0.75 mg/kg) was 4,197±756 ng/ml/min (*p=0.03) (Figure). Thus, while the dose of flecainide in the acetate formulation was 25% lower than in the HPβCD formulation, the time required to terminate AF (225%) and the AUC (239%) for flecainide acetate were double.ConclusionsThe HPβCD formulation more rapidly converted AF to NSR at a smaller AUC than the conventional flecainide acetate preparation. This finding suggests that the solubility enhancement by the cyclodextrin excipient could be advantageous in an oral inhalation solution to restore NSR in patients with AF.