PHARMACOLOGY OF THE CLASS-III ANTIARRHYTHMIC AGENT SEMATILIDE IN PATIENTS WITH ARRHYTHMIAS

Sematilide, a close structural analog of N-acetyl-procainamide, prolongs cardiac action potentials in vitro, whereas it does not depress maximum action potential upstroke slope, a "class III" action. This report outlines an evaluation of the clinical pharmacologic actions of sematilide in 14 patients with chronic high-frequency nonsustained ventricular arrhythmias. In all, 36 intravenous infusions (range 0.15 to 1.5 mg/kg over 15 minutes) were administered in a dose-ranging, placebo-controlled study design. Sematilide prolonged rate-corrected QT (QTc) in a dose- and concentration-related fashion, did not alter PR or QRS, and slowed heart rate at high concentrations (greater-than-or-equal-to 2-mu-g/ml). The relations between dose and total area under the time-concentration curve, dose and peak plasma concentration, and peak plasma concentration and increase in QTc were linear (r = 0.66 to 0.92; p < 0.001). QTc increases of congruent-to 25% were seen at plasma concentrations of congruent-to 2.0-mu-g/ml. The mean elimination half-life (+/- SD) was 3.6 +/- 0.8 hours, and most of a dose (77 +/- 13%) was recovered unchanged in the urine. Plasma concentrations greater-than-or-equal-to 0.8-mu-g/ml suppressed arrhythmias (5 patients) or aggravated them (3), including 1 patient who needed cardioversion for an episode of torsades de pointes (2.7-mu-g/ml). Thus, sematilide exerts class III actions in patients. Further studies to evaluate the role of this antiarrhythmic mode of action should be conducted at doses designed to limit QTc increases.