The positive frequency-dependent electrophysiological effects of the I Kur inhibitor XEN-D0103 are desirable for the treatment of atrial fibrillation

Background Selective inhibitors of K v 1.5 channels are being developed for the treatment of atrial fibrillation (AF). Objectives The purpose of this study was to investigate the effects of the highly selective K v 1.5 inhibitor XEN-D0103 on human atrial action potentials (APs) at high excitation rates and to assess safety. Methods Intracellular APs (stimulation rates 1–5 Hz) were measured in right atrial trabeculae from patients in sinus rhythm (SR), chronic AF (cAF; AF of u003e6 months duration), and paroxysmal AF (pAF). The safety and tolerability of XEN-D0103 were tested in a double-blind, randomized, placebo-controlled phase 1 study. Results Depending on its concentration, XEN-D0103 elevated the plateau potential. At 1 Hz, XEN-D0103 (3 µM) shortened action potential duration at 90% repolarization (APD 90 ) and effective refractory period (ERP) in SR preparations, but prolonged these parameters in cAF preparations. In SR and pAF preparations, the shortening effects on APD 90 and ERP turned into prolongation at high rates. In cAF trabeculae, XEN-D0103 prolonged APD 90 and ERP at 2 and 3 Hz. At high rates, more SR and pAF preparations failed to capture excitation in the presence of the drug than in its absence. XEN-D0103 (10 µM) did not significantly affect human ventricular APs. Even with plasma concentrations reaching 7000 ng/mL, XEN-D0103 did not increase ∆∆QTcF (QT interval corrected by the Fridericia formula) in the analysis of electrocardiograms of healthy volunteers, and no subjects receiving an active treatment had a QT or QTcF interval u003e450 ms, or increase in QTcF from baseline u003e30 ms. Conclusion APD prolongation and suppression of APs by XEN-D0103 at high stimulation rates in SR and pAF tissue, but not cAF, could be of therapeutic benefit for reducing AF burden. This concept needs to be confirmed in clinical trials.