Azimilide pharmacokinetics following intravenous and oral administration of a solution and capsule formulation

Azimilide dihydrochloride (NE-10064) is a novel class ill antiarrhythmic ag ent that blocks both the slowly and rapidly acting components of the delaye d rectifier potassium current of human atrial and ventricular myocytes. Ln clinical studies;azimilide reduced the frequency of symptomatic episodes of atrial fibrillation, atrial flutter, and paroxysmal supraventricular tachy cardia. This study was conducted to characterize azimilide pharmacokinetics following single-dose administration of a 1 mg/kg intravenous infusion (18 min), 2 mg/kg oral solution, and a 150 mg orally administered capsule. Thi s was a three-period randomized, crossover study in 27 healthy, drug-free ( including caffeine and alcohol), nonsmoking male volunteers (mean [SD] age, 25.9 [1.0] years; weight 74.3 [0.7] kg 23 Caucasians and 4 Hispanics). Blo od and urine samples were collected for 27 days and analyzed for azimilide using HPLC with UV detection. Subjects were monitored for adverse events an d abnormalities in clinical laboratory tests, vital signs, and electrocardi ography (including Holter monitoring). Mean (%CV) azimilide parameters were total clearance = 0.143 L/h/kg (38%), renal clearance = 0.014 L/h/kg (35%) ,steady-state volume of distribution = 13.2 L/kg(23%), and terminal exponen tial half-life = 78.8 h (44%). Similar parameter estimates were obtained fo llowing oral administration, Both the oral solution and capsule formulation s were completely absorbed. In addition, the rate (C-max) and extent of abs orption (AUC) following oral administration of the capsule dosage form were bioequivalent to the oral solution with means for times of maximum blood c oncentration of 7.08 and 7.18 hours for the oral solution and capsule, resp ectively. Azimilide dihydrochloride was generally well tolerated in all sub jects. (C) 1999 the American College of Clinical Pharmacology.