THERAPY AND PREVENTION Clinical pharmacology of propafenone

We determined the efficacy, pharmacokinetics, and plasma concentration-response relationships ofpropafenone, a promising new antiarrhythmic drug. Thirteen patients with frequent and complex ventricular premature beats were studied after receiving four 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 threefold from 300 to 900 mg/day. There was great intersubject variability in elimination half-life (mean 6 hr, 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 three parameters in individual patients determined the duration of the antiarrhythmic action of propafenone during washout (mean 11.5 hr, range 4 to 22). There was a greater than 90% reduction of ventricular premature beats in 10 subjects during dose ranging and in seven during double-blind crossover. Side effects requiring discontinuation of the drug occurred in three patients and included apparent worsening of arrhythmias in two. We conclude that 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. Circulation 68, No. 3, 589-596, 1983. PROPAFENONE is a promising new antiarrhythmic drug. In microelectrode experiments with guinea pig atria and sheep Purkinje cells, the drug slows the rate of rise of the action potential and decreases the action potential duration.",2 Propafenone also has weak ,Bblocking and Ca+ + antagonist properties in isolated tissues.1 Initial placebo-controlled trials in humans show that propafenone is effective for suppressing ventricular ectopic activity.4' Previous studies suggest that propafenone has a short half-life of 3 to 4 hr but that the duration of its antiarrhythmic effects may last longer.6'7 Studies with limited data have yielded con flicting information on the ability to predict antiarrhythmic effect from propafenone concentration.8' We undertook this study to assess the pharmacokinetic and pharmacodynamic profile of propafenone with special emphasis on evaluating the relationship between drug dose and plasma concentration as well as From the Cardiology Division, Stanford University Medical Center, Stanford. This study was supported by a grant from Knoll Pharmaceutical Company, Whippany, NJ. Dr. Connolly is supported by a grant from the Ontario Heart Foundation. Address for correspondence: Roger A. Winkle, M.D., Cardiology Division, Stanford University Medical Center, Stanford, CA 94305. Received Feb. 14, 1983; revision accepted May 5, 1983. between plasma concentration and antiarrhythmic effect.