Comparative analysis of the effects of rice and bread meals on bioavailability of itraconazole using NONMEM in healthy volunteers

Yun, Hyo-In; Baek, Min Sun; Park, In Sook; Choi, Bo Kyung; Kwon, Kwang‐il

doi:10.1007/s00228-006-0200-5

Cited by 16 publications

(11 citation statements)

References 17 publications

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“…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. 7 and Table 5).…”

Section: Discussionmentioning

confidence: 56%

“…Yun et al (11) suggest that the variability in fasting AUC across studies might be related to the volume of fluid administered with the dose. 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).…”

Section: Discussionmentioning

confidence: 99%

“…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: 56%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

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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“…Some of the first mathematical models used to assess the effects of the concomitant intake of food on pharmacokinetics were one- [ 41 ], two- [ 42 ], and three-compartment [ 43 ] distribution models. However, food as a categorical covariate in these models inadequately described the physiological changes in the gastrointestinal system in response to food consumption.…”

Section: Predicting Food Effectsmentioning

confidence: 99%

Food Effects on Oral Drug Absorption: Application of Physiologically-Based Pharmacokinetic Modeling as a Predictive Tool

Cheng

Wong

2020

Pharmaceutics

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The bioavailability of an orally administered small molecule is often dictated by drug-specific physicochemical characteristics and is influenced by many biological processes. For example, in fed or fasted conditions, the transit time within the gastrointestinal tract can vary, confounding the ability to predict the oral absorption. As such, the effects of food on the pharmacokinetics of compounds in the various biopharmaceutics classification system (BCS) classes need to be assessed. The consumption of food leads to physiological changes, including fluctuations in the gastric and intestinal pH, a delay in gastric emptying, an increased bile secretion, and an increased splanchnic and hepatic blood flow. Despite the significant impact of a drug’s absorption and dissolution, food effects have not been fully studied and are often overlooked. Physiologically-based pharmacokinetic (PBPK) models can be used to mechanistically simulate a compound’s pharmacokinetics under fed or fasted conditions, while integrating drug properties such as solubility and permeability. This review discusses the PBPK models published in the literature predicting the food effects, the models’ strengths and shortcomings, as well as future steps to mitigate the current knowledge gap. We observed gaps in knowledge which limits the ability of PBPK models to predict the negative food effects and food effects in the pediatric population. Overall, the further development of PBPK models to predict food effects will provide a mechanistic basis to understand a drug’s behavior in fed and fasted conditions, and will help enable the drug development process.

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Population In Vitro-In Vivo Correlation Model Linking Gastrointestinal Transit Time, pH, and Pharmacokinetics: Itraconazole as a Model Drug

et al. 2016

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Comparative analysis of the effects of rice and bread meals on bioavailability of itraconazole using NONMEM in healthy volunteers

Abstract: Therefore, although a dose of itraconazole is normally administered immediately after a meal to increase its bioavailability, this is not an effective strategy after a rice meal.

Cited by 16 publications

References 17 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

Food Effects on Oral Drug Absorption: Application of Physiologically-Based Pharmacokinetic Modeling as a Predictive Tool

Population In Vitro-In Vivo Correlation Model Linking Gastrointestinal Transit Time, pH, and Pharmacokinetics: Itraconazole as a Model Drug

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