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 micrograms/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 micrograms/kg produced significant dose-dependent prolongations of the QTc interval compared to placebo. Maximal mean QTc prolongations were 5 micrograms/kg, 29 ms (7%) at 2 h; 7.5 micrograms/kg, 35 ms (9%) at 6 h; and 10 micrograms/kg, 47 ms (12%). Following i.v. infusion of dofetilide (0.5 mg) (n = 9), the QTc interval significantly increased from 401 +/- 26 to 504 +/- 105 ms at the end of the infusion. One subject exhibited excessive prolongation of his QTc 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 QTc 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.(ABSTRACT TRUNCATED AT 250 WORDS)
Tham
T C
TC
Department of Therapeutics and Pharmacology, Queen's University of Belfast, Northern Ireland.
MacLennan
B A
BA
Burke
M T
MT
Harron
D W
DW
D000284:Administration, Oral; D000328:Adult; D000704:Analysis of Variance; D000889:Anti-Arrhythmia Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D004311:Double-Blind Method; D004562:Electrocardiography / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D010627:Phenethylamines / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D013449:Sulfonamides / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*
D000889:Anti-Arrhythmia Agents; D010627:Phenethylamines; D013449:Sulfonamides; C063533:dofetilide