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

• Published in: Journal of pharmaceutical sciences Vol. 93; no. 5; pp. 1279 - 1286
• Main Authors: Corey, Alfred E., Agnew, Jeffrey R., King, Eileen C., Parekh, Nikhil J., Powell, James H., Thompson, Gary A.
• Format: Journal Article
• Language: English
• Published: Hoboken Elsevier Inc 01.05.2004; Wiley Subscription Services, Inc., A Wiley Company; Wiley; American Pharmaceutical Association
• Subjects: Administration, Oral; Adult; Aged; azimilide; Biological and medical sciences; Confidence Intervals; Female; General pharmacology; hepatic impairment; Humans; Hydantoins; Imidazolidines - administration & dosage; Imidazolidines - pharmacokinetics; Liver Diseases - metabolism; Liver Diseases - physiopathology; Male; Medical sciences; Middle Aged; Pharmaceutical technology. Pharmaceutical industry; pharmacokinetics; Pharmacology. Drug treatments; Piperazines - administration & dosage; Piperazines - pharmacokinetics; hepatic impairment; pharmacokinetics; azimilide; Azimilide; Liver; Single dose; Furan derivatives; Oral administration; Piperazine derivatives; Pharmacokinetics
• ISSN: 0022-3549; 1520-6017
• DOI: 10.1002/jps.20060

Azimilide dihydrochloride (75–125mg/day) is currently being developed for use in prolonging the time to recurrence of atrial fibrillation/flutter and for reducing the frequency of shocks in patients with an implantable cardioverting defibrillator. This study investigated the influence of mild and moderate hepatic impairment on azimilide pharmacokinetics. Six subjects each with mild and moderate hepatic impairment (Child–Pugh grades A and B, respectively) were age, weight, smoking status, and gender-matched to a healthy subject (total N = 24). Each subject was administered a single, oral dose of 100mg azimilide dihydrochloride following an overnight fast. Blood/plasma and urine samples were collected up to 28 days and over 9 days, respectively, and analyzed using HPLC with MS/MS or UV detection. For azimilide, most parameters in subjects with mild to moderate hepatic impairment were within 25% of those observed in matched healthy subjects, with no statistically significant differences observed. For F-1292 (major metabolite in plasma), a significant decrease in AUC was observed in subjects with moderate hepatic impairment, secondary to an increase in renal clearance (CLr). Based on these results, no a priori dosage adjustment is required in subjects with mild to moderate hepatic impairment. © 2004 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 93:1279–1286, 2004