Increased Oral Bioavailability of Itraconazole and Its Active Metabolite, 7-Hydroxyitraconazole, When Coadministered With a Vitamin C Beverage in Healthy Participants

Bae, Soo Kyung; Park, Soojin; Shim, Eon-Jeong; Mun, Ji-Hyun; Kim, Eun Young; Shin, Jung Woog; Shon, Ji‐Hong

doi:10.1177/0091270010365557

Cited by 30 publications

(19 citation statements)

References 26 publications

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“…In addition, the dissolution of itraconazole is a function of GI pH, which is highly varied between and within subjects, even under fasted conditions (52,53). The variability in fed AUC also appears to be a function of the acid content and fat content of the meal (11,14). The standardized high-fat high-calorie breakfast in the present analysis behaved like the rice meal of Yun et al (11), with lower overall simulated AUC values in the fed state than those in the fasted state ( Fig.…”

Section: Discussionmentioning

confidence: 99%

“…Both itraconazole and hydroxyitraconazole have nonlinear kinetics in a comparison of single-versus multiple-dose administration (9,10). Various literature studies of the effect of food on itraconazole absorption showed that the absorption is highly varied between subjects, with considerable interstudy variability in the observed area under the concentration-time curve (AUC) values in the fed and fasted states (e.g., see references [11][12][13][14].…”

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confidence: 99%

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

Abuhelwa

Foster

Mudge

et al. 2015

Antimicrob Agents Chemother

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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...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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

Abuhelwa

Foster

Mudge

et al. 2015

Antimicrob Agents Chemother

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“…Itraconazole is a triazole antifungal, with activity against Candida species (including some fluconazole- 53 or vitamin C drink 54 ) at low gastric pH. Oral itraconazole solution has increased bioavailability (B30-35%) compared with the capsules, but in contrast to the capsules, is maximally absorbed during fasting.…”

Section: Triazole Antifungalsmentioning

confidence: 99%

Has the era of individualised medicine arrived for antifungals? A review of antifungal pharmacogenomics

Ashbee

Gilleece

2011

Bone Marrow Transplant

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“…Higher consumption of sugar-sweetened beverages (like coca cola) is associated with weight gain and increased risk for the development of type 2 diabetes mellitus, and caffeine is a psychoactive substance. In such situation, co-administration of vitamin C beverage and ITZ may be useful for achieving maximum absorption of ITZ in patients with drug-or disease-related gastric hypochlorhydria (pH [ 4) (Bae et al 2011). In addition, ITZ has been also found to be a substrate of P-glycoprotein (P-gp) (Balayssac et al 2005;Wang et al 2002).…”

Section: Introductionmentioning

confidence: 99%

Development of self emulsifying drug delivery system of itraconazole for oral delivery: formulation and pharmacokinetic consideration

Chudasama

Shah

Patel

et al. 2015

Journal of Pharmaceutical Investigation

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Poorly water-soluble drug, itraconazole (ITZ) offers a challenge in developing a drug product with adequate bioavailability. The potential for lipidic self-emulsifying drug delivery system to improve the oral bioavailability of ITZ was investigated in fasted rats. A series of ITZ SEDDS were prepared in three groups based on oil:S/CoS mixture ratios (1:9, 1:6 and 1:4) using Capryol 90 (oil), a mixture of Labrasol and Tween 20 (-surfactants) and Transcutol P (co-surfactant). The multicomponent delivery systems were optimized by evaluating their ability to self-emulsify when introduced in simulated gastric fluid, without pepsin, under gentle agitation and by determination of droplet size and visual observation. Three formulations (F5, F21 and F27), one from each group were selected based on droplet size and visual observation. The effect of oil and surfactants content on mean globule size of resulting emulsions was studied. It was clear that oil to surfactant and co-surfactant ratio has the main impact on the droplet size of the emulsion formed after dilution. However, the relation between droplet size and in vivo absorption of ITZ was futile. The order of AUC was 1:4 [ 1:6 [ 1.9 for oil:S/CoS mixture ratios. Following an oral administration of developed SEDDS and marketed capsule to rats, a 1.7, 2.0 and 2.33-fold increase in bioavailability was observed for F5, F21 and F27 respectively, compared with marketed capsule. The results from this study demonstrate the potential use of SEDDS to provide an effective way of improving oral absorption of lipophilic drugs.

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Increased Oral Bioavailability of Itraconazole and Its Active Metabolite, 7-Hydroxyitraconazole, When Coadministered With a Vitamin C Beverage in Healthy Participants

Cited by 30 publications

References 26 publications

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

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

Has the era of individualised medicine arrived for antifungals? A review of antifungal pharmacogenomics

Development of self emulsifying drug delivery system of itraconazole for oral delivery: formulation and pharmacokinetic consideration

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