Effect of Age and Gender on Azimilide Pharmacokinetics After a Single Oral Dose of Azimilide Dihydrochloride

Abstract

Azimilide is a new class III antiarrhythmic drug that blocks K+ channels. To determine the effects of age and gender on azimilide pharmacokinetics, a single 150-mg oral dose was administered to 66 healthy volunteers in a 3 x 2 factorial design (age groups of 18-40, 41-64, and > or = 65 years). Blood and urine were analyzed for azimilide and metabolites. The single dose was well-tolerated. Azimilide was 94% plasma protein-bound, and binding was not affected by age or gender. Age does not affect azimilide pharmacokinetics. The renal clearance of azimilide was significantly higher in women than in men (19%), but oral clearance did not differ between genders. Although the maximum azimilide concentration (Cmax) was 27% higher in women, time to maximum concentration or area under the azimilide concentration-time curve were not different from those for men. Body weight-adjusted Cmax did not differ between genders. Dosing adjustments based on either age or gender are not required.

Comparative oral bioavailability of azimilide dihydrochloride in the fed and fasted states

“…Azimilide pharmacokinetic parameters obtained in this study are consistent with those previously reported [2,3]. Azimilide is a low clearance drug [3] exhibiting extensive tissue distribution and these characteristics lead to a relatively long-terminal exponential half-life, which in this study was approximately 80 h. As in previous studies [2,3], renal clearance comprises a small percent of oral clearance (approximately 9%).…”

“…assay with u.v. absorbance detection (340 nm) was used to determine azimilide concentrations in blood and urine [2]. Whole blood cells were lysed by successive freezing and warming.…”

“…Clinical studies have demonstrated the drug is effective in reducing the frequency of symptomatic episodes in patients with atrial ®brillation, atrial¯utter and paroxysmal supraventricular tachycardia at a maintenance dose of 100 or 125 mg day x1 . Azimilide pharmacokinetics have been determined following intravenous and oral administration [2,3]. Results from these studies indicate that azimilide is extensively metabolized with renal clearance comprising approximately 10% of total clearance.…”

Effect of Mild and Moderate Hepatic Impairment on Azimilide Pharmacokinetics Following Single Dose Oral Administration

“…Blood samples (sodium heparin anticoagulated) were obtained prior to and at 0.5, 1, 2, 4, 5, 6, 7 (also used for plasma protein binding), 8,10,12, and 24 h and 2, 3, 4, 5, 6, 7, 8, 9, 10, 13, 16, 19, and 22 days post-dose. Additional blood samples were also collected at 25 and 28 days after dosing in hepatically impaired subjects.…”

“…2 Following intravenous administration, azimilide pharmacokinetic parameters include: total clearance ¼ 0.136 L/h/kg; renal clearance (CL r ) ¼ 0.013 L/h/kg; steady-state volume of distribution ¼ 12.9 L/kg; and a terminal exponential halflife ¼ 71.4 h. Azimilide plasma protein binding is about 94%, 3 is concentration independent over the range observed clinically and is predominately bound to albumin, with minor binding to alpha 1 acid glycoprotein. 4,5 These parameters indicate that azimilide has a low extraction ratio (low capacity clearance) with a steady-state volume of distribution consistent with extensive tissue distribution.…”