SELECTIVE I-K BLOCKER ALMOKALANT EXHIBITS CLASS III-SPECIFIC EFFECTS ON THE REPOLARIZATION AND REFRACTORINESS OF THE HUMAN HEART - A STUDY OF HEALTHY-VOLUNTEERS USING RIGHT-VENTRICULAR MONOPHASIC ACTION-POTENTIAL RECORDINGS

Almokalant, a recently developed potassium-channel blocker, has exhibited properties of a selective class III agent in vitro and in animal experiments. We report the first invasive study in humans in which the electrophysiological characteristics of almokalant were assessed. Thirty-four healthy males received bolus and maintenance infusions of almokalant to two of four target plasma concentrations of 20, 50, 100, and 150 nM. Electrophysiological variables were assessed during stimulation at 100 and 120 beats/min at baseline and at two consecutive targeted levels. Almokalant dose-dependently increased the duration of the monophasic action potential (MAP) above a mean plasma concentration of 60 nM. The duration at 90% repolarization significantly increased by 20% from baseline at 100 beats/min (p < 0.00005), and by 19% at 120 beats/min (p < 0.00005), at a mean plasma concentration of 116 nM. During atrial stimulation, there was a significant increase in the QT interval, amounting to 24% at 100 beats/min (p < 0.00005) and to 30% at 120 beats/min (p = 0.0006), at 124 nM. During right ventricular stimulation in the apical region, the QT interval significantly increased by 17% at 100 beats/min (p < 0.00005), and 13% at 120 beats/min (p < 0.00005). During stimulation from the right ventricular outflow tract, the QT interval increased to a lesser extent and significantly only at 120 beats/min: 9% at 100 beats/min (p = NS) and 6% at 120 beats/min (p = 0.001) at 118 nM. The effective refractory period (ERP) of the atria increased by 18% at 100 beats/min at 119 nM (p = 0.005). The right ventricular ERP increased by 16% at both heart rates (HR) (p < 0.00005) during stimulation from the apical region, and by 11% during stimulation from the outflow tract (p = 0.0001 at 100 beats/min and p = 0.0006 at 120 beats/min). There was no effect on the ERP of the atrioventricular node, (AVN) on the sinus node function or cardiac conduction. Two individuals experienced a transient metallic taste during bolus infusion aiming at 50 and 100 nM, but this side effect did not occur in the group receiving the highest doses. Pronounced T-wave/U-wave (TU) morphology changes were observed in 4 individuals. Almokalant exhibited characteristics of a pure class III agent with no effects on cardiac conduction or sinus node function when given intravenously. Although no proarrhythmias were observed, the development of TU morphology changes and increased spatial dispersion of repolarization after the highest doses warrants further studies regarding the safety profile of the drug.