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%ΔQT C , with mean EC 50 of 509 to 566 ng/mL. Peak circadian variation in QT C was equivalent to 14% of E max . Rapid equilibration occurred between blood and the biophase. Unconfounded pharmacodynamic estimates required inclusion of circadian QT c variation in the pharmacodynamic model.