KINETICS AND DYNAMICS OF SEMATILIDE

Sematilide HCl is a novel class III antiarrhythmic drug. The goals of this study in volunteers were to determine the pharmacokinetics, effec t (QTc interval), and tolerability after intravenous and oral administ ration of 25 mg of the drug. Plasma and urine concentrations were meas ured by a specific highperformance liquid chromatography method. Pharm acokinetic data analysis used a compartment model independent approach . An effect on QTc was observed only after intravenous administration, and its relationship to the plasma concentration showed a countercloc kwise hysteresis. A semiparametric approach was used to collapse the h ysteresis and then evaluate the effect-site-concentration-to-effect re lationship. After intravenous and oral administration, 75.1 (6.5)% (me an +/- SD) and 36.0 (11.5)% of the dose was excreted unchanged in urin e, respectively. The respective renal clearances were 250 (41) ml . mi n(-1) and 222 (44) ml . min(-1). The bioavailability of sematilide was 0.47 (0.15). A maximum percent effect on QTc of 12 (1)% occurred with a delay of 14 min after termination of an intravenous infusion of 10 min. After collapsing the hysteresis, the pharmacokinetic-pharmacodyna mic data could be fitted appropriately by a linear model in four subje cts and by an Emax model in two subjects. Sematilide HCl was well tole rated.