Influence of ketoconazole on azimilide pharmacokinetics in healthy subjects

To assess the influence of ketoconazole on azimilide pharmacokinetics.

A two-period randomized crossover study was conducted in healthy male and female subjects (19-45 years). Placebo or 200 mg ketoconazole were administered orally every 24 h for 29 days. On day 8, a single oral dose of 125 mg azimilide dihydrochloride was coadministered following an overnight fast. Blood samples were obtained prior to and for 22 days following azimilide dihydrochloride administration. The plasma protein binding of azimilide was also assessed at 6 h after dosing.

Following ketoconazole administration, a 16% increase in azimilide AUC (90% confidence interval (CI) 112%, 120%), a 12% increase in C(max) (95% CI 107%, 116%), a 13% increase in t(1/2,z) (95% CI 107%, 120%) and a 14% decrease in CL(o) (95% CI 82%, 90%) were observed.

The changes in azimilide pharmacokinetics following ketoconazole treatment are not clinically important since the 90% CI for the AUC fell within the prespecified range of 80-125%. Thus, no clinically important drug interactions are expected when azimilide dihydrochloride is coadministered with CYP3A4 inhibitors.