Clinical pharmacology of propafenone.

Abstract

The efficacy, pharmacokinetics and plasma concentration-response relationships of propafenone, a promising new antiarrhythmic drug were determined. Thirteen patients with frequent and complex ventricular premature beats were studied after receiving 4 increasing doses, during drug washout and during a randomized double-blind placebo-controlled trial, to evaluate the optimal dose in each patient. A nonlinear relationship was found between propafenone dose and steady-state mean concentration with a 10-fold increase in drug concentration as dose increased 3-fold from 300 to 900 mg/day. There was great intersubject variability in elimination half-life (mean 6 h, range 2.4 to 11.8), steady-state mean concentration on 900 mg/day of propafenone (mean 1008 ng/ml, range 482 to 1812), and therapeutic plasma concentration (mean 588 ng/ml, range 64 to 1044). The interaction of these 3 parameters in individual patients determined the duration of the antiarrhythmic action of propafenone during washout (mean 11.5 h, range 4-22). There was a > 90% reduction of ventricular premature beats in 10 subjects during dose ranging and in 7 during double-blind crossover. Side effects requiring discontinuation of the drug occurred in 3 patients and included apparent worsening of arrhythmias in two. Apparently, propafenone effectively suppresses ventricular arrhythmias and that nonlinear drug accumulation and intersubject variability in elimination of half-life, steady-state mean plasma concentration and therapeutic concentration indicate a need for individual therapy.