Effects of Food and Omeprazole on a Novel Formulation of Super Bioavailability Itraconazole in Healthy Subjects

Abstract

To address the limited bioavailability and intolerance of the conventional itraconazole (ITZ) formulations, a new formulation labeled super bioavailability (SUBA) itraconazole has been developed; however, the specific effects of food and gastric pH are unknown. This study evaluated the pharmacokinetic profile of SUBA itraconazole under fasting and fed conditions, as well as with the concomitant administration of a proton pump inhibitor. First, the effect of food was assessed in an open-label, randomized, crossover bioavailability study of 65-mg SUBA itraconazole capsules (2 65-mg capsules twice a day) in healthy adults (n = 20) under fasting and fed conditions to steady-state levels. Second, an open-label, two-treatment, fixed-sequence comparative bioavailability study in healthy adults (n = 28) under fasted conditions compared the pharmacokinetics of a single oral dose of SUBA itraconazole capsules (2 65-mg capsules/day) with and without coadministration of daily omeprazole delayed-release capsules (1 40-mg capsule/day) under steady-state conditions. In the fed and fasted states, SUBA itraconazole demonstrated similar concentrations at the end of the dosing interval, with modestly lower total and peak ITZ exposure being shown when it was administered under fed conditions than when it was administered in the fasted state, with fed state/fasted state ratios of 78.09% (90% confidence interval [CI], 74.49 to 81.86%) for the area under the concentration-time curve over the dosing interval (14,183.2 versus 18,479.8 ng · h/ml), 73.05% (90% CI, 69.01 to 77.33%) for the maximum concentration at steady state (1,519.1 versus 2,085.2 ng/ml), and 91.53% (90% CI, 86.41 to 96.96%) for the trough concentration (1,071.5 versus 1,218.5 ng/ml) being found. When dosed concomitantly with omeprazole, there was a 22% increase in the total plasma exposure of ITZ, as measured by the area under the concentration-time curve from time zero to infinity (P = 0.0069), and a 31% increase in the peak plasma exposure of ITZ, as measured by the maximum concentration (P = 0.0083).

Open-Label Crossover Oral Bioequivalence Pharmacokinetics Comparison for a 3-Day Loading Dose Regimen and 15-Day Steady-State Administration of SUBA-Itraconazole and Conventional Itraconazole Capsules in Healthy Adults

“…Neither formulation achieved ITZ C max_ss or trough levels that would suggest toxicity, based on previous reports. In addition, the 65-mg S-ITZ formulation achieved levels similar to those achieved under a fed condition by Lindsay et al (1). The steady-state trough levels from this study obtained by administering the 65-mg S-ITZ formulation were also similar to those achieved in other studies of the 50-mg S-ITZ formulation approved in Australia, Europe, and South America (14,26).…”

“…The adverse events observed in these studies were similar to those previously described with S-ITZ (1,8,14,26). Mild gastrointestinal complaints (nausea or abdominal pain), headache, and transaminase level elevation are all well described with the use of ITZ and lead to treatment discontinuation.…”

“…The U.S. FDA-approved prescribing information for S-ITZ recommends that it be taken with food; however, only moderate food effects were observed, as the minimum drug levels after administration prior to the subsequent dose (C trough ) in the fed and fasted states are within 10% of each other (5). When a single dose of S-ITZ was coadministered with a proton pump inhibitor after establishing its steady state, an increase in ITZ plasma exposure was observed (1). These are key attributes that may be helpful in patients with subtherapeutic ITZ serum drug concentrations due to poor absorption of C-ITZ capsule formulations.…”

Aspiring Antifungals: Review of Current Antifungal Pipeline Developments

“…It has been shown to significantly increase oral bioavailability (173%) while reducing interpatient variability compared to traditional oral formulation [11]. Additionally, there is little food or acid effect on the bioavailability with this novel formulation, a significant advance over conventional itraconazole [12].…”

Blastomycosis

“…A new oral formulation, SUBA-itraconazole (for SUperBioAvailable), has been developed by dispersing microencapsulated nanoparticles of itraconazole onto a polymer matrix, which allows for improved absorption of the drug. 94 The SUBA-itraconazole capsule contains 65-mg itraconazole, and the dosage recommended is 130 mg twice daily.…”