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Pharmacokinetic and pharmacodynamic modeling of the effects of oral and intravenous administrations of dofetilide on ventricular repolarization
Author(s) -
Coz Franck Le,
FunckBrentano Christian,
Morell Thierry,
Ghadanfar Mathieu M.,
Jaillon Patrice
Publication year - 1995
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1016/0009-9236(95)90038-1
Subject(s) - dofetilide , pharmacokinetics , qt interval , medicine , pharmacodynamics , crossover study , anesthesia , pharmacology , placebo , alternative medicine , pathology
Objectives To examine the pharmacokinetics and the relation between plasma concentrations of the new potassium channel blocker dofetilide and 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 minutes) in a randomized crossover study. The QT c interval versus dofetilide plasma concentration was analyzed by use of pharmacokinetic and pharmacodynamic modeling techniques. Results Dofetilide absolute bioavailability and systemic clearance were 92% ± 9% and 0.35 ± 0.05 L/hr/kg, respectively. Mean maximum increase in QT c interval duration was 99 msec (27%) and 61 msec (16%) after intravenous and oral administration, respectively. A counterclockwise hysteresis loop between dofetilide plasma concentrations and QT c interval duration was observed after intravenous infusions in all subjects, whereas direct linear relationships were observed after oral administrations in eight of 10 subjects. Pharmacokinetic‐pharmacodynamic modeling showed the consistency of the effect versus concentration relationships obtained with the two routes of administration. With use of a maximum effect (E max ) model and data obtained after intravenous infusion, mean maximum QT c prolongation (E max ) was 121 ± 57 msec and mean dofetilide plasma concentration associated with half the maximum effect (EC 50 ) was 2.2 ± 0.6 ng/ml. Pharmacokinetic‐pharmacodynamic modeling was useful in detecting 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 postdistribution data. Conclusion We conclude that dofetilide prolongs QT c interval 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 dofetilide. Clinical Pharmacology & Therapeutics (1995) 57 , 533–542; doi: