Pharmacokinetics and electrocardiographic effects of a new controlled-release form of flecainide acetate: Comparison with the standard form and influence of the CYP2D6 polymorphism*

Abstract

Objectives Our objectives were study the single‐ and repeated‐dose pharmacokinetics and electrocardiographic effects (QRS duration) of a new controlled‐release form offlecainide 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 and0.89 ± 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. Maximumand 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 withmean plasma concentration for both forms (pooled data; P < .001). The 95% confidence interval for this regression was 26% narrower for the controlled‐release form thanfor 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 newcontrolled‐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 Pharmacology & Therapeutics (2002) 72, 112–122; doi: 10.1067/mcp.2002.125946