PHARMACOKINETICS OF SEMATILIDE IN RENAL-FAILURE

A randomized, two-period, two-treatment study was conducted to investi gate the effect of renal impairment on the pharmacokinetics of the Cla ss III antiarrhythmic sematilide HCl. The pharmacokinetic-pharmacologi c effect relationship and tolerability of sematilide HCl were also stu died. The study included 22 subjects: 6 healthy volunteers and 16 pati ents with various degrees of renal impairment, including functionally anephric patients on intermittent hemodialysis. Separated by a 14-day washout period, the subjects received a constant rate intravenous infu sion of 40 mg sematilide HCl over 30 minutes and a tablet containing 1 00 mg of the drug. The functionally anephric patients were studied dur ing and off dialysis after intravenous and oral administration of the drug, respectively. Blood and urine samples were collected at defined times up to 48 hours and 72 hours, respectively, after administration. Sematilide concentrations in plasma, urine, and dialysate were measur ed by a validated high-performance liquid chromatography (HPLC) method with ultraviolet detection. The pharmacokinetic data analysis used a compartment model independent approach. The heart rate-corrected Lead II QT interval was recorded as a pharmacologic endpoint. Subjective sy mptoms, cardiovascular parameters, routine serum chemistry, and hemato logy and urinalysis parameters were measured to assess tolerability. M ean renal clearance after intravenous and oral administration was redu ced in patients with severe renal impairment, Statistically significan t linear correlations existed between total clearance of sematilide an d creatinine clearance for all subjects who could be evaluated after b oth intravenous and oral administration. Steady-state volume of distri bution, absolute bioavailability, and nonrenal clearance of sematilide were independent of renal function. The mean dialysis clearance was 9 8 mL/min, indicating effective removal of the drug by hemodialysis, in accord with the drug's Class III pharmacologic activity, the heart ra te corrected Lead II QT intervals were prolonged in all subjects after intravenous and oral administration of the drug. The pharmacologic ef fect to plasma concentration relationship in renal patients and in hea lthy subjects was comparable. Based on the experimentally determined l inear relationship between total clearance of sematilide and creatinin e clearance, modified dose regimens for sematilide HCl in patients wit h renal impairment and functionally anephric patients off hemodialysis were developed.