Bioequivalence study of two formulations of itraconazole 100 mg capsules in healthy volunteers under fed conditions: a randomized, three-period, reference-replicated, crossover study

Dragojević-Simić, Viktorija; Kovacevic, Aleksandra; Jacević, Vesna; Rančić, Nemanja; Djordjević, Snežana; Kilibarda, Vesna; Mikov, Momir; Bokonjić, Dubravko

doi:10.1080/17425255.2018.1503649

Cited by 7 publications

(17 citation statements)

References 22 publications

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“…o.o., Belgrade, Serbia (Kanazol ® ). The bioequivalence of the two products has been proven ( Dragojević-Simić et al, 2018 ).…”

Section: Methodsmentioning

confidence: 99%

“…The study was strictly conducted in accordance with the principles of ICH GCP and the latest version of the Helsinki Declaration. It is an academic study based on a bioequivalence study on two oral formulations of itraconazole previously approved, performed, and published ( Dragojević-Simić et al, 2018 ).…”

Section: Methodsmentioning

confidence: 99%

“…Informed written consent was obtained before any procedure was performed. All the procedures involving healthy volunteers were already described ( Dragojević-Simić et al, 2018 ). Briefly, the selection was based on their medical and medication history, physical examination (body weight, body height, arterial blood pressure, pulse rate, and electrocardiogram), and clinical laboratory evaluation (hematology, biochemistry, urinalysis, human immunodeficiency virus and hepatitis C antibodies, hepatitis B surface antigen, and serum pregnancy test, female only).…”

Section: Methodsmentioning

confidence: 99%

“…Therefore, therapeutic drug monitoring (TDM) would timely and appropriately guide dose modifications ( Allegra et al, 2017 ; John et al, 2019 ). As a result of its variable pharmacokinetics, itraconazole is known as a highly variable drug (HVD), meaning that its within-subject variability for PK parameters, the maximum plasma concentration of drug (C max ), and area under the concentration-time curve (AUC), is larger than 30% ( European Medicines Agency, 2010 ; Dragojević-Simić et al, 2018 ; Endrenyi and Tothfalusi, 2019 ). However, sources of its pharmacokinetics variability are not yet fully elucidated, and age, body mass index, ethnicity, sex, and different pharmaceutical formulations are probably involved ( Fagiolino et al, 2007 ; Allegra et al, 2017 ).…”

Section: Introductionmentioning

confidence: 99%

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Influence of Gender, Body Mass Index, and Age on the Pharmacokinetics of Itraconazole in Healthy Subjects: Non-Compartmental Versus Compartmental Analysis

et al. 2022

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Itraconazole is a triazole antifungal agent with highly variable pharmacokinetics, with not yet fully identified factors as the source of this variability. Our study aimed to examine the influence of body mass index, gender, and age on the first dose pharmacokinetics of itraconazole in healthy subjects, using pharmacokinetic modeling, non-compartmental versus compartmental ones. A total of 114 itraconazole and hydroxy-itraconazole sets of plasma concentrations of healthy subjects of both genders, determined using a validated liquid chromatographic method with mass spectrometric detection (LC-MS), were obtained for pharmacokinetic analyses performed by the computer program Kinetica 5®. Genetic polymorphism in CYP3A4, CYP3A5, CYP1A1, CYP2C9, and CYP2C19 was analyzed using PCR-based methods. Multiple linear regression analysis indicated that gender had a significant effect on AUC as the most important pharmacokinetics endpoint, whereas body mass index and age did not show such an influence. Therefore, further analysis considered gender and indicated that both geometric mean values of itraconazole and hydroxy-itraconazole plasma concentrations in men were prominently higher than those in women. A significant reduction of the geometric mean values of Cmax and AUC and increment of Vd in females compared with males were obtained. Analyzed genotypes and gender differences in drug pharmacokinetics could not be related. Non-compartmental and one-compartmental models complemented each other, whereas the application of the two-compartmental model showed a significant correlation with the analysis of one compartment. They indicated a significant influence of gender on itraconazole pharmacokinetics after administration of the single oral dose of the drug, given under fed conditions. Women were less exposed to itraconazole and hydroxy-itraconazole than men due to poorer absorption of itraconazole, its more intense pre-systemic metabolism, and higher distribution of both drug and its metabolite.

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“…o.o., Belgrade, Serbia (Kanazol ® ). The bioequivalence of the two products has been proven ( Dragojević-Simić et al, 2018 ).…”

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Influence of Gender, Body Mass Index, and Age on the Pharmacokinetics of Itraconazole in Healthy Subjects: Non-Compartmental Versus Compartmental Analysis

et al. 2022

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“…From the available literatures, it is very well established that itraconazole has high intra-subject variability. Due to its high intra-subject variability, the available studies were conducted by partial/ complete replicate design (SBOA, 2010;Suarez-Kurtz et al, 1999;Dragojević-Simić et al, 2018).…”

Section: Safety and Tolerability Pro Ilementioning

confidence: 99%

Assessment of comparative bioavailability of Itraconazole capsule 100 mg under fasting conditions by average bioequivalence (ABE), population bioequivalence (PBE) and individual bioequivalence (IBE) approaches

Micheal

Sayana³

et al. 2019

ijrps

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The assessment of interchangeability (prescribability and switchability) is one of the debatable topics in the generic drug industry. Currently, the question is whether we have an adequate assessment system for the evaluation of generic drug products. The objective of the study is to assess the comparative oral bioavailability of Itraconazole capsule 100mg after administering single dose to adult, healthy, human subjects in fasted state by different bioequivalence approaches like average bioequivalence (ABE), population bioequivalence (PBE) and individual bioequivalence (IBE) and to monitor the safety of study subjects. An open-label, balanced, randomized, two-treatment, two-sequence, four-period, crossover, single-dose comparative oral bioavailability study was conducted in sixteen healthy, adult, human subjects in a fasted state. Test formulation, Itraconazole capsule 100mg, and reference formulation, SPORANOX® (Itraconazole) capsule 100mg, were administered in a fasted state. The test formulation, Itraconazole capsule 100mg, showed bio-inequivalent against reference SPORANOX® (Itraconazole) capsule 100mg in study subjects under a fasted state. Also, the test formulation exhibited a similar safety and tolerability profile compared to the reference formulation. There was no report of serious adverse events (SAEs) and deaths in the study. The test formulation was found to be bio-inequivalent to reference formulation in the study subjects under a fasted state by estimating different bioequivalence approaches like average bioequivalence, population bioequivalence, and individual bioequivalence.

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Prediction of gastric pH‐mediated drug exposure using physiologically‐based pharmacokinetic modeling: A case study of itraconazole

Yang

Lee

2023

CPT Pharmacom & Syst Pharma

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Abnormal gastric acidity, including achlorhydria, can act as a significant source of variability in orally administered drugs especially with pH‐sensitive solubility profiles, such as weak bases, potentially resulting in an undesirable therapeutic response. This study aimed to evaluate the utility of physiologically‐based pharmacokinetic (PBPK) modeling in the prediction of gastric pH‐mediated drug exposure by using itraconazole, a weak base, as a case. An itraconazole PBPK model was developed on the mechanistic basis of its absorption kinetics in a middle‐out manner from a stepwise in vitro‐in vivo extrapolation to in vivo refinement. Afterward, an independent prospective clinical study evaluating gastric pH and itraconazole pharmacokinetics (PKs) under normal gastric acidity and esomeprazole‐induced gastric hypoacidity was conducted for model validation. Validation was performed by comparing the predicted data with the clinical observations, and the valid model was subsequently applied to predict PK changes under achlorhydria. The developed itraconazole PBPK model showed reasonable reproducibility for gastric pH‐mediated exposure observed in the clinical investigation. Based on the model‐based simulations, itraconazole exposure was expected to be decreased up to 65% under achlorhydria, and furthermore, gastric pH‐mediated exposure could be mechanistically interpreted according to sequential variation in total solubility, dissolution, and absorption. This study suggested the utility of PBPK modeling in the prediction of gastric pH‐mediated exposure, especially for drugs whose absorption is susceptible to gastric pH. Our findings will serve as a leading model for further mechanistic assessment of exposure depending on gastric pH for various drugs, ultimately contributing to personalized pharmacotherapy.

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Bioequivalence study of two formulations of itraconazole 100 mg capsules in healthy volunteers under fed conditions: a randomized, three-period, reference-replicated, crossover study

Abstract: The use of the reference-scaling approach with 3-period design (TRR, RTR, and RRT) was an efficient way to demonstrate that two commercially available oral itraconazole formulations met the predetermined bioequivalence criteria.

Cited by 7 publications

References 22 publications

Influence of Gender, Body Mass Index, and Age on the Pharmacokinetics of Itraconazole in Healthy Subjects: Non-Compartmental Versus Compartmental Analysis

Influence of Gender, Body Mass Index, and Age on the Pharmacokinetics of Itraconazole in Healthy Subjects: Non-Compartmental Versus Compartmental Analysis

Assessment of comparative bioavailability of Itraconazole capsule 100 mg under fasting conditions by average bioequivalence (ABE), population bioequivalence (PBE) and individual bioequivalence (IBE) approaches

Prediction of gastric pH‐mediated drug exposure using physiologically‐based pharmacokinetic modeling: A case study of itraconazole

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