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

Abstract

Aims This study investigated the relative oral bioavailability of azimilide dihydrochloride following administration in the fed (high-fat meal) and fasted states. Methods This was a single-dose, randomized, two-way crossover study in 30 healthy, Caucasian, male subjects. Following oral administration, blood samples were collected over 27 days and analysed for azimilide using h.p.l.c. with u.v. detection. Pharmacokinetic parameters were determined using`noncompartmental' analysis and compared using an ANOVA and 90% or 95% con®dence intervals. Results The extent of absorption was equivalent in the fed and fasted states (ratio = 96.2%; 90% CI=90.5% x102.4%). However, C max was decreased 19% following a high-fat meal (ratio=81.4%; 90% CI=76.2% x87.0%). No difference in t max or t K,z was observed. Conclusions Azimilide dihydrochloride may be orally administered to patients without regard to the prandial state.

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

“…2,3,6,16 Although the results appear to differ between the two groups of subjects with normal hepatic function, they are generally similar to the range of mean/geometric mean values reported in previous studies (AUC (ng  h/ mL), 7316-9735; C max (ng/mL), 100-138; and T 1/2,z (h), 80-123). 2,3,6,16 Comparison of demographics, smoking history, and laboratory parameters between the two control groups provided no explanation for these apparent differences. Nonetheless, since the a priori statistical analysis was based on differences between age, weight, smoking status, and gender matched subjects, these apparent differences do not affect the overall conclusions from this study.…”

“…Following oral administration, azimilide is completely absorbed with peak blood concentrations occurring at approximately 7 h. When azimilide is administered following a high fat meal, no change in extent of absorption is observed although the peak blood concentrations decrease approximately 19%. 6 The majority of azimilide clearance is due to metabolic processes with CL r only accounting for approximately 10%. Metabolites include F-1292, F-1292 b-acyl glucuronide, a desmethyl metabolite, a carboxylic acid metabolite, an N-oxide metabolite, and other metabolites formed following cleavage of azimilide.…”

Influence of Coadministration on the Pharmacokinetics of Azimilide Dihydrochloride and Digoxin

“…Heparinized blood samples for measurement of blood azimilide concentrations were obtained just prior to dosing on days 1 through 5, at 7 hours postdose on days 1 through 4, and at 0.5, 1, 2, 3, 4, 5, 6,7,8,10,12,14,24,36,48,72,96,120,144,168,192,216,240,264,288,312,336,360,384,408,432,456, and 480 hours postdose on day 5. Blood samples were stored frozen at or below -20°C and protected from light until analyzed.…”

“…meal, no change in extent of absorption is observed, although peak blood concentration decreases approximately 19%. 6 Azimilide clearance is primarily due to metabolic processes, with renal clearances accounting for only approximately 10%. Metabolites include F-1292 (4chlorophenylfuroic acid), F-1292 β-acyl glucuronide, a desmethyl metabolite, a carboxylic acid metabolite, an N-oxide metabolite, and other metabolites formed following cleavage of azimilide.…”

Influence of ketoconazole on azimilide pharmacokinetics in healthy subjects

“…Owing to its low clearance and large volume of distribution, azimilide has a long terminal exponential half-life. Following oral administration, azimilide is completely absorbed with peak blood concentrations occurring at approximately 7 h. When azimilide is administered following a high fat meal, no change in the extent of absorption is observed, although peak blood concentrations decrease by 19% [3].…”