MK-0448, a Specific Kv1.5 Inhibitor Safety, Pharmacokinetics, and Pharmacodynamic Electrophysiology in Experimental Animal Models and Humans

Background-We evaluated the viability of I-Kur as a target for maintenance of sinus rhythm in patients with a history of atrial fibrillation through the testing of MK-0448, a novel I-Kur inhibitor. Methods and Results-In vitro MK-0448 studies demonstrated strong inhibition of I-Kur with minimal off-target activity. In vivo MK-0448 studies in normal anesthetized dogs demonstrated significant prolongation of the atrial refractory period compared with vehicle controls without affecting the ventricular refractory period. In studies of a conscious dog heart failure model, sustained atrial fibrillation was terminated with bolus intravenous MK-0448 doses of 0.03 and 0.1 mg/kg. These data led to a 2-part first-in-human study: Part I evaluated safety and pharmacokinetics, and part II was an invasive electrophysiological study in healthy subjects. MK-0448 was well-tolerated with mild adverse experiences, most commonly irritation at the injection site. During the electrophysiological study, ascending doses of MK-0448 were administered, but no increases in atrial or ventricular refractoriness were detected, despite achieving plasma concentrations in excess of 2 mu mol/ L. Follow-up studies in normal anesthetized dogs designed to assess the influence of autonomic tone demonstrated that prolongation of atrial refractoriness with MK-0448 was markedly attenuated in the presence of vagal nerve simulation, suggesting that the effects of I-Kur blockade on atrial repolarization may be negated by enhanced parasympathetic neural tone. Conclusions-The contribution of I-Kur to human atrial electrophysiology is less prominent than in preclinical models and therefore is likely to be of limited therapeutic value for the prevention of atrial fibrillation. (Circ Arrhythm Electrophysiol. 2012;5:1193-1201.)