Flecainide acetate: concentration-response relationships for antiarrhythmic and electrocardiographic effects

In order to evaluate the concentration-response relationship for either antiarrhythmic or electrocardiographic effects, 13 patients with symptomatic, stable, premature ventricular contractions (> 100/hour) were selected, and flecainide was administered as a single oral dose (200 mg) and as chronic treatment (150 mg b.i.d. for 21 days). In both settings a Holter monitoring, serial electrocardiogram (ECG) tracings and serum samples for flecainide concentrations were obtained; the relationships between drug levels, antiarrhythmic efficacy, and ECG modifications were analysed. The results obtained indicated that QRS and PR intervals lengthened significantly either after acute oral administration or after chronic treatment by 21-36% (mean values), and that the QRS interval changes were significantly correlated to serum flecainide concentrations (r = 0.68, p < 0.001 after acute and r = 0.79, p < 0.001 after chronic administration). However, for any given plasma concentration of flecainide, the percentage widening of QRS intervals was smaller after chronic treatment, as shown by the different slopes of the correlation lines (7.7 +/- 4.0% ml.micrograms -1 after acute dosing versus 3.8 +/- 1.1% ml.micrograms -1 after chronic treatment, p < 0.001). This finding suggests a relative reduction of flecainide's effects on ECG intervals during chronic treatment, while the antiarrhythmic efficacy was maintained (flecainide effective in 8/13 patients in acute and in 11/13 patients in chronic) without significant differences between flecainide's minimal effective concentrations (262 +/- 119 ng/ml and 319 +/- 276 ng/ml for acute vs chronic respectively). We conclude that during chronic treatment a dissociation seems to occur between the electrocardiographic and the antiarrhythmic effects and this could limit the clinical usefulness of monitoring QRS intervals.