Pharmacokinetics and electrocardiographic effects of a new controlled-release form of flecainide acetate: comparison with the standard form and influence of the CYP2D6 polymorphism.
OBJECTIVE
Our objectives were study the single- and repeated-dose pharmacokinetics and electrocardiographic effects (QRS duration) of a new controlled-release form of flecainide acetate compared with the immediate-release form and to examine the influence of CYP2D6 activity.


METHODS
Twenty-four healthy subjects (6 men and 6 women at both dosages) received single and repeated doses of 100 or 200 mg immediate-release and controlled-release flecainide in a randomized crossover design. Electrocardiograms were recorded and flecainide plasma concentrations were measured before administration and up to 96 hours after administration.


RESULTS
The controlled-release formulation had sustained-release properties, with a significantly lower maximum concentration (C(max)) and delayed time to reach C(max). Compared with the immediate-release formulation, the relative bioavailability of the controlled-release formulation at steady state was 0.85 +/- 0.17 and 0.89 +/- 0.17 for the 100-mg/day and 200-mg/day doses, respectively. Trough flecainide plasma concentration at steady state was bioequivalent for both formulations. Maximum and minimum QRS increases were not significantly different for either the immediate-release or the controlled-release form of flecainide after administration of both single and repeated doses. Mean QRS duration during a dosing interval at steady state correlated with mean plasma concentration for both forms (pooled data; P <.001). The 95% confidence interval for this regression was 26% narrower for the controlled-release form than for the immediate-release form. Flecainide-induced QRS prolongation and pharmacokinetics were not significantly influenced by CYP2D6 activity.


CONCLUSIONS
Flecainide-induced QRS prolongation did not differ between the new controlled-release form and the immediate-release form. Flecainide plasma concentrations associated with the new controlled-release form predicted QRS prolongation with less variability compared with the immediate-release form. The CYP2D6 polymorphism did not appear to influence flecainide disposition kinetics or electrocardiographic effects at steady state.
Clinical Investigation Center, Division of Clinical Pharmacology, Saint-Antoine University Hospital, 184 rue du Faubourg Saint-Antoine, 75571 Paris Cedex, France.
Laurent
L
Tennezé
Eliane
E
Tarral
Nicole
N
Ducloux
Christian
C
Funck-Brentano
D000328:Adult; D000889:Anti-Arrhythmia Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D001682:Biological Availability; D018592:Cross-Over Studies; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics / Q000378:metabolism*; D003692:Delayed-Action Preparations; D004334:Drug Administration Schedule; D004562:Electrocardiography / Q000187:drug effects; D005260:Female; D005424:Flecainide / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D006329:Heart Conduction System / Q000187:drug effects*; D006801:Humans; D008297:Male; D011110:Polymorphism, Genetic; D012016:Reference Values
D000889:Anti-Arrhythmia Agents; D003692:Delayed-Action Preparations; D019389:Cytochrome P-450 CYP2D6; D005424:Flecainide