Population Pharmacokinetic Modeling of Itraconazole and Hydroxyitraconazole for Oral SUBA-Itraconazole and Sporanox Capsule Formulations in Healthy Subjects in Fed and Fasted States

Abstract

bItraconazole is an orally active antifungal agent that has complex and highly variable absorption kinetics that is highly affected by food. This study aimed to develop a population pharmacokinetic model for itraconazole and the active metabolite hydroxyitraconazole, in particular, quantifying the effects of food and formulation on oral absorption. Plasma pharmacokinetic data were collected from seven phase I crossover trials comparing the SUBA-itraconazole and Sporanox formulations of itraconazole. First, a model of single-dose itraconazole data was developed, which was then extended to the multidose data. Covariate effects on itraconazole were then examined before extending the model to describe hydroxyitraconazole. The final itraconazole model was a 2-compartment model with oral absorption described by 4-transit compartments. Multidose kinetics was described by total effective daily dose-and time-dependent changes in clearance and bioavailability. Hydroxyitraconazole was best described by a 1-compartment model with mixed first-order and Michaelis-Menten elimination for the single-dose data and a time-dependent clearance for the multidose data. The relative bioavailability of SUBA-itraconazole compared to that of Sporanox was 173% and was 21% less variable between subjects. Food resulted in a 27% reduction in bioavailability and 58% reduction in the transit absorption rate constant compared to that with the fasted state, irrespective of the formulation. This analysis presents the most extensive population pharmacokinetic model of itraconazole and hydroxyitraconazole in the literature performed in healthy subjects. The presented model can be used for simulating food effects on itraconazole exposure and for performing prestudy power analysis and sample size estimation, which are important aspects of clinical trial design of bioequivalence studies. Itraconazole is a broad-spectrum orally active triazole antifungal used for both prophylaxis and treatment of systemic fungal infections (1, 2). Itraconazole exerts antifungal activity through the inhibition of fungal cytochrome P450 (CYP) 3A isoenzymes, which mediate the synthesis of ergosterol, a vital component of the fungal cell membrane (3). Itraconazole undergoes extensive hepatic metabolism by human CYP3A4 isoenzymes. Both itraconazole and its major active metabolite, hydroxyitraconazole, inhibit mammalian CYP3A4, although to a lesser extent than that with the fungal CYP3A isoenzymes (4).Itraconazole is currently available as oral capsules in two marketed formulations: Sporanox, the brand product (Janssen Pharmaceuticals, Inc.[5]), and SUBA-itraconazole, the alternative product. SUBA-itraconazole is a novel formulation containing a solid dispersion of itraconazole in a pH-dependent polymeric matrix to enhance its dissolution and intestinal absorption; therefore, it exhibits greater bioavailability than the innovator product. As of 30 June 2015, SUBA-itraconazole has marketing approval in Australia, Spain, Germany, Sweden, and United Kingdom; currently, it is ava...

International Evaluation of MIC Distributions and Epidemiological Cutoff Value (ECV) Definitions for Fusarium Species Identified by Molecular Methods for the CLSI Broth Microdilution Method

“…Lower posaconazole and voriconazole ECVs were calculated for F. verticillioides (2 and 4 g/ml, respectively) and the F. oxysporum SC (8 and 16 g/ml, respectively). These triazole ECVs are mostly higher than the expected maximal, variable, and dose-dependent trough levels of each of the agents (23,24,40) and highlight the intrinsically resistant nature of Fusarium spp. The same applies to amphotericin B values.…”

“…Successful therapeutic treatment of invasive disease is usually associated with neutrophil recovery, a major factor in making the setting of clinical breakpoints so challenging. The new formulations of itraconazole and posaconazole have improved bioavailability and reduced variability in exposure among subjects (23,24). However, the efficacy of these formulations in the treatment of fusariosis has not been established.…”

The antifungal pipeline: a reality check

“…The anticancer properties of itraconazole come from its inhibition of both angiogenesis and Hedgehog signalling 124 . However, the new nanosuspension formulation has improved bioavailability 125 , so it might be co-opted again by clinicians for its antifungal activity, and Mayne Pharma could direct efforts towards its development in the antifungal arena. Finally, antifungal agents and basic antiseptic chemicals have been altered to make formulations that can be aerosolized for delivery into the lungs 126 , including new powder formulations 127 , or incorporated into formulations that can attack yeast biofilms on foreign bodies and could therefore be used as antifungal solutions or coatings to preserve catheters 128 .…”

Aspiring Antifungals: Review of Current Antifungal Pipeline Developments

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“…While significant effort has been made in identifying novel antifungal compounds and classes, there has also been progress in optimizing the agents within the present antifungal arsenal. Itraconazole is a broad spectrum triazole, but its clinical utilization has been hampered by severely limited bioavailability [10,11]. Traditional oral itraconazole capsules have a bioavailability of approximately 55% when administered with food, but this is reduced in patients with an elevated gastric pH (i.e., on acid suppression therapy) and exhibits significant variability between patients.…”