Influence of dofetilide on QT-interval duration and dispersion at various heart rates during exercise in humans

Background The objective of this study was to assess the influence of heart rate on QT-interval duration and dispersion during administration of the new selective potassium-channel blocker dofetilide in normal subjects. Methods and Results Dofetilide 0.25 and 0.75 mg was administered for 4 days to 12 subjects in a randomized-sequence, double-blind, three-period, placebo-controlled, crossover study. QT-RR pairs were measured on study day 4 over a wide range of RR intervals obtained at rest and during an exercise test. QT-interval durations were calculated at seven predetermined RR intervals ranging from 400 ms (150 bpm) to 1000 ms (60 bpm) by use of monoexponential nonlinear curve fitting. QT(max) and QT(min) were calculated similarly, and QT-interval dispersion was measured as QT(max)-QT(min) at each predetermined RR interval. Minimal effects were found with 0.25 mg dofetilide. Two hours after administration of 0.75 mg dofetilide, QT interval was prolonged by 16.7 +/- 8.7% at a heart rate of 60 bpm (P<.01) and by 7.4 +/- 8.2% at a heart rate of 150 bpm (P<.05). QT prolongation at a heart rate of 150 bpm was less pronounced than at lower heart rates. Neither placebo nor dofetilide at either dose significantly increased QT-interval dispersion at any heart rate. Conclusions Dofetilide increases QT-interval duration but does not increase QT-interval dispersion in healthy subjects. QT-interval prolongation remains significant at high heart rates, although some degree of reverse rate dependence is observed at high concentrations.