Population Pharmacokinetics of Itraconazole in Thai HIV-1-Infected Persons

Koks, C. H. W.; Huitema, Alwin D. R.; Kroon, Eugène; Chuenyam, Theshinee; Sparidans, Rolf W.; Lange, Joep M. A.; Beijnen, Jos H.

doi:10.1097/00007691-200304000-00014

Cited by 16 publications

(12 citation statements)

References 12 publications

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“…Population pharmacokinetic models of itraconazole kinetics in the literature to date have used linear elimination kinetics (35)(36)(37)(38)(39)(40). Linear itraconazole kinetics was also found for the model of single-dose data developed in this analysis, but this model underpredicted multidose concentrations, suggesting a deviation from the assumption of linearity outside the single-dose setting.…”

Section: Discussionmentioning

confidence: 99%

“…For studies HGN007, HGN008, 10850702, and 10850703, blood samples (ϳ7 ml) for the determination of itraconazole and hydroxyitraconazole concentrations were taken at 0, 0.5, 1, 1.5, 2, 2.5, 3,4,5,6,8,10,12,24,36,48, and 72 h after the dose. Study HGN008 had additional samples collected at 96 and 120 h. A similar but more extensive pharmacokinetic (PK) sampling schedule for the determination of itraconazole was performed for study MPG009, with additional samples collected at 3.5, 4.5, 5.5, 6.5, 7, 9, 16, 96, and 120 h.…”

Section: Methodsmentioning

confidence: 99%

“…Blood samples for a determination of itraconazole and hydroxyitraconazole concentrations were taken at Ϫ48, Ϫ24, 0, 0.5, 1, 1.5, 2, 2.5, 3,4,5,6,8,10,12,24,36,48, and 72 h, all relative to the time after dose on day 15.…”

Section: Methodsmentioning

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%

Section: Methodsmentioning

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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“…The CL/F of oral solution for 30 adults with cystic fibrosis as reported by the same author was 30 L (13). In another population study of 11 HIV positive patients in Thailand, the CL/F of capsule formulation was 28 L/h (14). It is known that the bioavailability of ITZ capsule formulation is about 55% (15), while that of the oral solution is slightly higher.…”

Section: Discussionmentioning

confidence: 99%

Population pharmacokinetics of intravenous itraconazole in patients with persistent neutropenic fever

Lee¹,

Chae

Park³

et al. 2009

Journal of Clinical Pharmacy and Therapeutics

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Purpose: Empirical use of intravenous (IV) itraconazole (ITZ) for febrile neutropenic patients has recently been introduced in Korea. This study was designed to investigate the population pharmacokinetics (PK) of IV-ITZ. Methods: Sparse PK data were collected from febrile neutropenic patients undergoing empirical ITZ therapy at 200 mg ⁄ day after loading doses. NONMEM (Version. 5AE1AE1) was used to estimate population PK parameters. Results: Forty-two patients were enrolled in the study. Mean population CL and V of IV-ITZ were 10 L ⁄ h and 1050 L, respectively. Body weight was the only contributing covariate of CL. The median simulated trough concentration of ITZ after 10 days was predicted to be about 700 ng ⁄ mL. Conclusions: In this study, we explored the population PK profile of ITZ given in IV formulation. We found that the current dosage regimen of IV-ITZ (200 mg ⁄ day) was appropriate to obtain therapeutic trough concentrations for neutropenic patients in Korea.

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“…Recent studies have described concentration-time profiles using linear pharmacokinetic models [29,33,34]; in these particular circumstances, the absence of nonlinearity is probably a function of study design. Oxidative metabolism of itraconazole produces hydroxyitraconazole in a ratio of approximately 1 : 1; the latter has comparable antifungal potency to the parent.…”

Section: Pharmacology and Pharmacokineticsmentioning

confidence: 99%