PHARMACOKINETIC AND PHARMACODYNAMIC MODELING OF THE EFFECTS OF ORAL AND INTRAVENOUS ADMINISTRATIONS OF DOFETILIDE ON VENTRICULAR REPOLARIZATION

Objectives: To examine the pharmacokinetics and the relation between p lasma concentrations of the new potassium channel blocker dofetilide a nd QT(c) prolongation on the surface electrocardiogram after oral and intravenous administration. Methods: Ten healthy volunteers received a single dose of 0.5 mg dofetilide orally and intravenously (over 30 mi nutes) in a randomized crossover study. The QT(c) interval versus dofe tilide plasma concentration was analyzed by use of pharmacokinetic and pharmacodynamic modeling techniques. Results: Dofetilide absolute bio availability and systemic clearance were 92% +/- 9% and 0.35 +/- 0.05 L/hr/kg, respectively. Mean maximum increase in QT(c) interval duratio n was 99 msec (27%) and 61 msec (16%) after intravenous and oral admin istration, respectively. A counterclockwise hysteresis loop between do fetilide plasma concentrations and QT(c) interval duration was observe d after intravenous infusions in all subjects, whereas direct linear r elationships were observed after oral administrations in eight of 10 s ubjects. Pharmacokinetic-pharmacodynamic modeling showed the consisten cy of the effect versus concentration relationships obtained with the two routes of administration. With use of a maximum effect (E(max)) mo del and data obtained after intravenous infusion, mean maximum QT(c) p rolongation (E(max)) was 121 +/- 57 msec and mean dofetilide plasma co ncentration associated with half the maximum effect (EC(50)) was 2.2 /- 0.6 ng/ml. Pharmacokinetic-pharmacodynamic modeling was useful in d etecting the maximum effect and in describing the plasma concentration versus effect relationship during intravenous infusion of dofetilide but was otherwise not superior to analyses performed with postdistribu tion data. Conclusion: We conclude that dofetilide prolongs QT(c) inte rval duration in a concentration-dependent manner in normal volunteers during sinus rhythm and that pharmacokinetic-pharmacodynamic modeling is useful for examination of maximum QT(c) prolongation induced by do fetilide.