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(Circulation. 1996;94:1592-1599.)
© 1996 American Heart Association, Inc.

Articles

Influence of Dofetilide on QT-Interval Duration and Dispersion at Various Heart Rates During Exercise in Humans

Jean-Louis Demolis, MD; Christian Funck-Brentano, MD, PhD; Jacques Ropers, PharmD; Mathieu Ghadanfar, MD; Donald J. Nichols, PhD; Patrice Jaillon, MD

the Clinical Pharmacology Unit, Saint-Antoine University Hospital, Paris, France; the Pfizer Clinical Research Group (M.G.), Paris La Defense, France; and Pfizer Central Research (D.J.N.), Sandwich, United Kingdom.

Correspondence to Patrice Jaillon, Unite de Pharmacologie Clinique, Hopital Saint-Antoine, 184 rue du Faubourg Saint-Antoine, 75012 Paris, France.

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.

Key Words: antiarrhythmia agents • drugs • potassium

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