Pharmacokinetics and pharmacodynamics following intravenous doses of azimilide dihydrochloride

Azimilide pharmacokinetics and pharmacodynamics were characterized in a saf ety and tolerance study of intravenously administered azimilide dihydrochlo ride. This was a parallel-group design (seven treatments), and 68 healthy v olunteers 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 in fusion doses were also given over 15 or 30 minutes. Blood and urine specime ns were collected and analyzed for azimilide and metabolites. QT(c) was mea sured as a marker of class III antiarrhythmic activity. Azimilide pharmacok inetics were dose proportional and did not differ among infusion rates. Azi milide 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 circadi an variation in QT(c) was equivalent to 14% E-max. Rapid equilibration occu rred between blood and the biophase. Unconfounded pharmacodynamic estimates required inclusion of circadian QT(c), variation in the pharmacodynamic mo del. (C) 1999 the American College of Clinical Pharmacology.