The pharmacokinetics and pharmacodynamics of oral dofetilide after twice daily and three times daily dosing

Aims The pharmacokinetics and pharmacodynamics of oral dofetilide, a novel, class III antiarrhythmic drug, were assessed during administration either twice or three times daily. Methods Dofetilide was administered orally to three groups of healthy subjects in daily doses of 1000 mu g (n = 8), 1500 mu g (n = 8), or 2500 mu g (n = 9) as twice daily and three times daily treatment regimens, with the two regimens assigned randomly as a two-way crossover for each subject and separated by at least a 6 day washout period. Results Pharmacokinetic analysis indicated a rise in plasma dofetilide concentrations until steady state was attained on day 3. C-trough had a linear dependence on dose for both the twice daily and three times daily dosing regimens. The maximum concentration attained (C-max) and the area under the concentration vs time curve (AUC(0,tau) increased linearly with dose for each dosing regimen on both days 1 and 5 of dosing. C-max occurred at 2 h. Pharmacodynamic measurements showed that the QTc interval increased in a dose-dependent manner and that the time to maximum QTc was 2 h after dosing. A linear relationship was determined between plasma dofetilide concentration and the prolongation of the QTc interval. The slope of this line was significantly greater on day 1 (ranging from 12.9 to 14.2 ms/ng ml(-1)) than on day 5 (ranging from 9.9 to 12.8 ms/ng ml(-1)). Conclusions The pharmacokinetics and pharmacodynamics of dofetilide are predictable and based on a linear relationship for both twice daily and three times daily dosing regimens. The QT responsiveness to dofetilide is greater on day 1 than on day 5.