Electrophysiological Characterization and Antiarrhythmic Efficacy of the Mixed Potassium Channel-Blocking Antiarrhythmic Agent AZ13395438 In Vitro and In Vivo

Abstract

To examine the electrophysiological, hemodynamic, and antiarrhythmic effects of the novel antiarrhythmic agent AZ13395438. The ion channel-blocking potency of AZ13395438 was assessed in Chinese hamster ovary cells stably expressing various human cardiac ion channels and in human atrial myocytes. The in vivo electrophysiological, hemodynamic, and antiarrhythmic effects of intravenously administered AZ13395438 were examined in anesthetized rabbits, in anesthetized naive dogs, and in dogs subjected to rapid atrial pacing (RAP) for 8 weeks. Pharmacokinetic/pharmacodynamic (PKPD) modeling was applied to predict the potency of AZ13395438 in increasing atrial and ventricular refractoriness. AZ13395438 potently and predominantly blocked the atrial repolarizing potassium currents I(Kur), I(Ach), and I(to) in vitro. In vivo, AZ13395438 caused a concentration-dependent and selective increase in atrial refractoriness with no or small effects on ventricular refractoriness and repolarization and on hemodynamics in both rabbits and dogs. The PKPD modeling predicted unbound plasma concentrations of AZ13395438 of 0.20 ± 0.039, 0.38 ± 0.084, and 0.34 ± 0.057 µmol/L to increase the right atrial effective refractory period by 20 milliseconds in the rabbit and in the naive and the RAP dogs, respectively. In the RAP dog with atrial fibrillation (AF), AZ13395438 significantly increased AF cycle length and successfully converted AF to sinus rhythm in 12 of the 12 occasions at an unbound plasma concentration of 0.48 ± 0.076 µmol/L. During saline infusion, conversion was seen only in 4 of the 10 occasions (P = .003 vs AZ13395438). Furthermore, AZ13395438 reduced AF inducibility by burst pacing from 100% to 25% (P < .001). AZ13395438 can be characterized as a mixed potassium ion channel-blocking agent that selectively prolongs atrial versus ventricular refractoriness and shows promising antiarrhythmic efficacy in a clinically relevant animal model of AF.