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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. QTc 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 Emax, ranged from 23 to 28%δQTc, with mean EC50 of 509 to 566 ng/mL. Peak circadian variation in QTc was equivalent to 14% of Emax. Rapid equilibration occurred between blood and the biophase. Unconfounded pharmacodynamic estimates required inclusion of circadian QTc variation in the pharmacodynamic model.