Influence of ketoconazole on azimilide pharmacokinetics in healthy subjects

Abstract

AimTo assess the influence of ketoconazole on azimilide pharmacokinetics. MethodsA 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. ResultsFollowing 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. ConclusionsThe 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.

Preparation and delayed release of poly(lactide‐ co‐glycolide)/ketoconazole composite fiber mats

“…The outstanding characteristics of KCZ have broad antimicrobial spectrum and strong antibacterial activity. Currently, it is widely used to treat superficial and internal fungus with significant effects such as tinea corporis, onychomycosis, colpitis, psoriasis, seborrheic dermatitis, hemorrhoid, and so on [1–4]. But the clinical application of KCZ is limited because oral KCZ can easily cause side effects, and most serious and lethal adverse reactions are related to the dose of oral KCZ.…”

Effects of ketoconazole on the pharmacokinetics of lenvatinib (E7080) in healthy participants

“…The broad‐spectrum antifungal agent ketoconazole is a potent and specific inhibitor of CYP3A4, and a p‐glycoprotein inhibitor . At therapeutic doses, ketoconazole has been shown to significantly alter plasma concentrations of CYP3A4 substrates . Assuming CYP3A4‐mediated metabolism accounts for ∼80% of lenvatinib total clearance, ketoconazole inhibition of CYP3A4 could result in a ≥90% reduction in CYP3A4‐mediated metabolism of lenvatinib and increase lenvatinib half‐life (t ½ ) ≥3‐fold.…”

“… 17 At therapeutic doses, ketoconazole has been shown to significantly alter plasma concentrations of CYP3A4 substrates. 18 , 19 Assuming CYP3A4-mediated metabolism accounts for ∼80% of lenvatinib total clearance, ketoconazole inhibition of CYP3A4 could result in a ≥90% reduction in CYP3A4-mediated metabolism of lenvatinib 19 and increase lenvatinib half-life (t ½ ) ≥3-fold. Ketoconazole was routinely used to evaluate drug interactions involving CYP3A4 inhibition mechanisms, including TKIs, 2 – 4 , 20 , 21 until October 16th 2013, when the United States Food and Drug Administration (FDA) recommended the use of alternate CYP3A inhibitors due to the risk of serious side effects with ketoconazole use.…”