Pharmacodynamic effect of continuous vs intermittent dosing of dofetilide on QT interval

To investigate the pharmacokinetics and pharmacodynamics of dofetilide 1 mg twice daily continuously for 24 days compared with intermittent single dose treatments.

A randomized, single-blinded, placebo-controlled, parallel-group, multiple-dose study design was utilized. Healthy male volunteer subjects were randomized into three groups. Group 1 received dofetilide 1.0 mg twice daily for 23 days and once on day 24. Group 2 received matching placebo capsules under the same regimen as group 1. Group 3 received a single dose of dofetilide 1.0 mg on days 1, 5, 10, 17, and 24 with identical placebo capsules administered at all other times to match the dosing pattern of the other groups.

Continuous administration of dofetilide resulted in the achievement of steady-state concentrations by day 5. Pharmacokinetic parameters following intermittent treatment showed no accumulation. Maximum daily QTc interval (mean +/- s.e. mean) increased in response to continuous twice-daily dofetilide from baseline (373 +/- 5) to day 2 (453 +/- 9) but thereafter decreased slightly, but not beyond day 5, by which time the mean maximum QTc was 440 +/- 7 ms. In contrast, single doses of dofetilide in the intermittently treated group led to reproducible increases in QTc. Thus mean (+/- s.e. mean) maximum QTc increased from a baseline of 387 +/- 7-467 +/- 14, 467 +/- 18, 469 +/- 14 and 458 +/- 10 ms on days 5, 10, 17 and 24, respectively. In view of the pharmacokinetic accumulation on continuous dosing, the attenuation of responsiveness is best represented by the slope of the QTc vs plasma concentration relationship. In the continuously treated group, an initial decrease in the value of the mean slope between day 1 (14.2 +/- 1.7 ms/ng ml(-1)) and day 5 (9.1 +/- 0.8 ms/ng ml(-1)) did not progress beyond day 5. The mean difference in slopes (95% CI) between the intermittent and continuously treated groups were 4.4 (1.3, 7.4) on day 5, 4.9 (1.6, 8.2) on day 10, 5.2 (1.1, 9.2) on day 17 and 4.4 (0.4, 8.4) on day 24.

With continuous twice-daily administration the QT interval responsiveness to dofetilide is greater after the first dose than it is at steady state. After day 5 the relationship between dofetilide plasma concentration and its QT interval effect is predictable and stable over time.