Effect of mild and moderate hepatic impairment on azimilide pharmacokinetics following single dose oral administration.

Azimilide dihydrochloride (75-125 mg/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 100 mg 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 (CL(r)). Based on these results, no a priori dosage adjustment is required in subjects with mild to moderate hepatic impairment.