Pharmacokinetics and pharmacodynamics following intravenous doses of azimilide dihydrochloride

Azimilide pharmacokinetics and pharmacodynamics were characterized in a safety and tolerance study of intravenously administered azimilide dihydrochloride. This was a parallel-group design (seven treatments), and 68 healthy volunteers received the drug. Single intravenous infusion doses (4.5 to 9 mg/kg) were administered over 60 minutes, and single 4.5 mg/kg intravenous infusion doses were also given over 15 or 30 minutes. Blood and urine specimens were collected and analyzed for azimilide and metabolites. QT(c) was measured as a marker of class III antiarrhythmic activity. Azimilide pharmacokinetics were dose proportional and did not differ among infusion rates. Azimilide pharmacodynamics did not differ among treatments. Mean E-max ranged from 23 to 28%Delta QT(c), with mean EC50 of 509 to 566 ng/mL. Peak circadian variation in QT(c) was equivalent to 14% E-max. Rapid equilibration occurred between blood and the biophase. Unconfounded pharmacodynamic estimates required inclusion of circadian QT(c), variation in the pharmacodynamic model. (C) 1999 the American College of Clinical Pharmacology.