title: The positive frequency-dependent electrophysiological effects of the IKur inhibitor XEN-D0103 are desirable for the treatment of atrial fibrillation.
abstract: BACKGROUND
  Selective inhibitors of Kv1.5 channels are being developed for the treatment of atrial fibrillation (AF).
  
  
  OBJECTIVE
  The purpose of this study was to investigate the effects of the highly selective Kv1.5 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 >6 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 (APD90) and effective refractory period (ERP) in SR preparations, but prolonged these parameters in cAF preparations. In SR and pAF preparations, the shortening effects on APD90 and ERP turned into prolongation at high rates. In cAF trabeculae, XEN-D0103 prolonged APD90 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 >450 ms, or increase in QTcF from baseline >30 ms.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Xention Ltd, Cambridge, United Kingdom.
authors.forename: John
authors.initials: J
authors.lastname: Ford
authors.affiliation: Xention Ltd, Cambridge, United Kingdom.
authors.forename: James
authors.initials: J
authors.lastname: Milnes
authors.affiliation: Xention Ltd, Cambridge, United Kingdom.
authors.forename: Said
authors.initials: S
authors.lastname: El Haou
authors.affiliation: Department of Pharmacology and Toxicology, Medical Faculty Carl Gustav Carus, Dresden, Germany.
authors.forename: Erich
authors.initials: E
authors.lastname: Wettwer
authors.affiliation: Department of Pharmacology and Toxicology, Medical Faculty Carl Gustav Carus, Dresden, Germany.
authors.forename: Simone
authors.initials: S
authors.lastname: Loose
authors.affiliation: Clinic for Cardiac Surgery, Heart Center Dresden, Dresden, Germany.
authors.forename: Klaus
authors.initials: K
authors.lastname: Matschke
authors.affiliation: Institut de Recherches Internationales Servier, Suresnes, France.
authors.forename: Benoit
authors.initials: B
authors.lastname: Tyl
authors.affiliation: Xention Ltd, Cambridge, United Kingdom.
authors.forename: Patrick
authors.initials: P
authors.lastname: Round
authors.affiliation: Department of Pharmacology and Toxicology, Medical Faculty Carl Gustav Carus, Dresden, Germany. Electronic address: ravens@rcs.urz.tu-dresden.de.
authors.forename: Ursula
authors.initials: U
authors.lastname: Ravens
mesh_terms: D000200:Action Potentials / Q000187:drug effects*; D000328:Adult; D000889:Anti-Arrhythmia Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D001281:Atrial Fibrillation / Q000175:diagnosis / Q000188:drug therapy / Q000503:physiopathology; D051668:Delayed Rectifier Potassium Channels / Q000037:antagonists & inhibitors*; D004562:Electrocardiography / Q000379:methods; D022062:Electrophysiologic Techniques, Cardiac / Q000379:methods; D064368:Healthy Volunteers; D006325:Heart Atria / Q000187:drug effects / Q000503:physiopathology; D006801:Humans; D008297:Male; D012032:Refractory Period, Electrophysiological / Q000187:drug effects*; D016896:Treatment Outcome
chemical_list: D000889:Anti-Arrhythmia Agents; D051668:Delayed Rectifier Potassium Channels
keywords: Atrial fibrillation; Frequency dependence; Human atrial action potentials; I(Kur) inhibitor XEN-D0103; QTc; QTcF