We determined the efficacy, pharmacokinetics, and plasma concentration-response relationships of propafenone, 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. between plasma concentration and antiarrhythmic effect. MethodsProtocol design. Patients with high-frequency ventricular premature beats (VPBs) were candidates for this study if they did not have disabling angina, heart failure, or unstable intercurrent illness. A complete history was obtained, physical and laboratory examinations were performed, and a baseline 48 hr ambulatory electrocardiogram (ECG) was taken to establish a minimum baseline VPB frequency of B 1440 VPBs/24 hr after antiarrhythmic drugs had been discontinued for at least five half-lives. Digoxin was continued in one patient with atrial fibrillation, and propranolol was continued in one pat...
Propafenone disposition kinetics were studied after intravenous and oral doses in patients with ventricular arrhythmias. Plasma concentration-time data were fit to a two-compartment model for all but one patient, whose data required fitting to a three-compartment model. The model-independent calculated values of clearance, steady-state volume of distribution, and terminal t1/2 were 11.2 +/- 4.8 ml/min/kg, 3.6 +/- 2.1 l/kg, and 5.0 +/- 3.6 hr. After 5 days on oral propafenone, elimination t1/2 was 6.2 +/- 3.3 hr. The longer t1/2s and the estimates of steady-state bioavailability above 100% suggests that clearance decreases during chronic oral dosing. Considerable intersubject variability was noted in all disposition parameters.
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