PHARMACODYNAMICS AND PHARMACOKINETICS OF THE CLASS-III ANTIARRHYTHMIC AGENT DOFETILIDE (UK-68,798) IN HUMANS

The pharmacodynamics, pharmacokinetics, safety, and tolerance of the class III antiarrhythmic dofetilide (UK-68,798) were evaluated in two groups of healthy volunteers; first, single oral escalating doses (1, 2, 5, 7.5, and 10 mug/kg with random insertion of placebo) were administered in a double-blind manner and, second, its intravenous (0.5 mg) and oral (0.5 mg) administration were compared in an open two-way crossover design. Oral dofetilide from 5 mug/kg produced significant dose-dependent prolongations of the QT(c) interval compared to placebo. Maximal mean QT(c) prolongations were 5 mug/kg, 29 ms (7%) at 2 h; 7.5 mug/kg, 35 ms (9%) at 6 h; and 10 mug/kg, 47 ms (12%). Following i.v. infusion of dofetilide (0.5 mg) (n = 9), the QT(c) interval significantly increased from 401 +/- 26 to 504 +/- 105 ms at the end of the infusion. One subject exhibited excessive prolongation of his QT(c) interval (451-808 ms) 5 min after the infusion, which was associated with an asymptomatic run (5 beats) of polymorphic ventricular tachycardia and several multifocal ventricular ectopic beats. Following oral administration of dofetilide (0.5 mg) (n = 9), the QT(c) interval increased significantly from 396 +/- 27 ms to a maximum of 445 +/- 27 ms at 2 +/- 0.9 h postdosing. No changes occurred in PR intervals and QRS width. Small changes occurred in the heart rate and blood pressure. The plasma elimination half-lives of dofetilide were found to be 7.5 +/- 0.4 (i.v.) and 7.1 +/- 0.2 (oral) h; the volume of distribution was 228 +/- 17 L; the clearance was 347 +/- 20 ml/min; 52 +/- 2% was recovered in the urine in the 48 h following dosing. The oral/i.v. bioavailability was 96% (range of 83-108%). Plasma concentrations of dofetilide increased in a dose-dependent manner. In conclusion, dofetilide has selective class III activity with an acceptable hemodynamic and pharmacokinetic profile and warrants further evaluation in humans.