MK-0448, a Specific Kv1.5 Inhibitor

Abstract

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 μmol/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.)

Cardiac ion channels

“…One compound, MK-0448, that is selective for Kv1.5 over other cardiac ion channels, showed efficacy in multiple preclinical models of AF and was examined in an invasive electrophysiological study in healthy volunteers. 47 In this study, MK-0448 did not prolong the atrial refractory period. Follow-up studies in anesthetized dogs attributed the lack of effect to the high vagal tone in young, healthy subjects such as those participating in the study.…”

“…Follow-up studies in anesthetized dogs attributed the lack of effect to the high vagal tone in young, healthy subjects such as those participating in the study. 47 Although vagal tone may be reduced in the patient population, the greater risk for episodes of AF associated with vagal stimulation does not bode well for this mechanism, and clinical development of MK-0448 was discontinued. However, a recent study with MK-0448 in human atrial tissue from sinus rhythm controls and from permanent AF patients showed that MK-0448 delayed the effective refractory period in atrial tissue from AF patients and not from control subjects.…”

Rate-Dependent Role of I Kur in Human Atrial Repolarization and Atrial Fibrillation Maintenance

“…Furthermore, the mechanism of I Kur in dog atrium is different from that in humans, and the magnitude is often very small (34). MK-0448 failed to prolong AERP in healthy human subjects using relatively slow stimulation cycle lengths of 400 and 600 ms at which I Kr recruitment balances I Kur block (35). I Kur block ratedependence, as described in this study, along with speciesand remodeling-related differences, likely account for these conflicting results.…”

Cardiac Potassium Channel Subtypes: New Roles in Repolarization and Arrhythmia

“…It is worth keeping in mind that chronic AF in humans might reduce K V 1.5 expression and thereby I Kur density (78,439). Also it should be mentioned that the importance of I Kur in humans seems to be less pronounced than suggested from preclinical animal models (336). In addition, I Kur density is diminished at high atrial heart rates as seen in AF (122).…”