In Silico Prediction of Plasma Concentrations of Fluconazole Capsules with Different Dissolution Profiles and Bioequivalence Study Using Population Simulation

Duque, Marcelo Dutra; Silva, Daniela Amaral; Issa, Michele Georges; Porta, Valentina; Löbenberg, Raimar; Ferraz, Humberto Gomes

doi:10.3390/pharmaceutics11050215

Cited by 19 publications

(10 citation statements)

References 29 publications

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“…The manufacture of f luconazole tablets were approved by FDA in 1990, when the biowaiver criteria did not exist yet, consequently, the development of fluconazole reference product was carried out only in SGF for dissolution test as evidenced in its patent (Fekete et al, 2005). Recently, Marcelo Dutra and co-workers showed that the dissolution profile of two comparator products batches assessed in SGF did not have similar dissolution profiles (Duque et al, 2019). Another study carried out in Peru using the fluconazole Brazilian reference product showed that no formulation met the criteria for f2 calculation.…”

Section: Resultsmentioning

confidence: 99%

Comparator product issues for biowaiver implementation: the case of Fluconazole

Lazo

Teleginski

Maciel

et al. 2022

Braz. J. Pharm. Sci.

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The aim of this work was to assess if the commercially available Fluconazole drug products (Reference, Generic and Similar) would meet the biowaiver criteria from Food and Drug Administration (FDA) and Brazilian Agency for Health Surveillance (ANVISA) agencies. All formulations were evaluated considering the dissolution profile carried out in Simulated Gastric Fluid (SGF) pH 1.2, Acetate Buffer (AB) pH 4.5 and Simulated Intestinal Fluid (SIF) pH 6.8. The results demonstrated that all formulations fulfilled the 85% of drug dissolved at 30 min criterion in SGF pH 1.2. However, in AB pH 4.5 and SIF pH 6.8, some formulations, including the comparator, did not achieve this dissolution percentage. The discrepant dissolution profiles also failed the ƒ2 similarity factor analysis, since none of the formulations showed values between 50 and 100 in the three dissolution media. Comparative dissolution profiles were not similar, considering that the main issues concerning the dissolution were evidenced for the comparator product. Hence, a revision in the regulatory norms in order to establish criteria to switch the comparator could result in an increased application of drugs based on biowaiver criteria.

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Section: Resultsmentioning

confidence: 99%

Comparator product issues for biowaiver implementation: the case of Fluconazole

Lazo

Teleginski

Maciel

et al. 2022

Braz. J. Pharm. Sci.

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“…Quite recently an in-silico modeling approach (the “Mechanistic Physiologically-Based Biopharmaceutics Modeling”) was used to predict the in vivo concentrations of ibuprofen through the use of a mechanistic oral absorption model built in the Phoenix WinNonlin ® software and coupled with the GastroPlus ® simulator [ 68 ]. Similarly, aiming at predicting the possibility of bioequivalence for fluconazole capsules, Duque et al, utilized dissolution profiles in order to simulate plasma levels and then evaluate their bioequivalence, using Population Simulator TM in GastroPlus ® [ 41 ]. This study showed that computer simulations can be an important tool to predict the probability of BE for fluconazole capsules.…”

Section: Discussionmentioning

confidence: 99%

“…In addition, computer simulations have been applied in bioequivalence in order to address issues like the use of parent drugs or metabolite, the statistical framework, and the development of scaled BE limits [ 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 ]. In addition, modeling and simulation approaches have appeared in the literature using in vitro dissolution data for the prediction of in vivo pharmacokinetic profiles, such as assessing the impact of dissolution variability on in vivo pharmacokinetic profile or to evaluate BE of fluconazole capsules [ 40 , 41 ].…”

Section: Introductionmentioning

confidence: 99%

An In Vitro–In Vivo Simulation Approach for the Prediction of Bioequivalence

Vlachou

Karalis

2021

Materials

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The aim of this study was to develop a new in vitro–in vivo simulation (IVIVS) approach in order to predict the outcome of a bioequivalence study. The predictability of the IVIVS procedure was evaluated through its application in the development process of a new generic product of amlodipine/irbesartan/hydrochlorothiazide. The developed IVIVS methodology is composed of three parts: (a) mathematical description of in vitro dissolution profiles, (b) mathematical description of in vivo kinetics, and (c) development of joint in vitro–in vivo simulations. The entire programming was done in MATLAB® and all created scripts were validated through other software. The IVIVS approach can be implemented for any number of subjects, clinical design, variability and can be repeated for thousands of times using Monte Carlo techniques. The probability of success of each scenario is recorded and finally, an overall assessment is made in order to select the most suitable batch. Alternatively, if the IVIVS shows reduced probability of BE success, the R&D department is advised to reformulate the product. In this study, the IVIVS approach predicted successfully the BE outcome of the three drugs. During the development of generics, the IVIVS approach can save time and expenses.

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“…In vitro dissolution studies are essential in BE testing; however, studies indicated that the lower limit in the ƒ 2 (i.e., 50) should be further lowered to match observed in vivo BE results [4,16,22,24]. Moreover, the one-point estimate for ƒ 2 , together with the dissolution model-independent approach (i.e., not being mechanistic in nature) are considered drawbacks of this approach.…”

Section: Similarity and Difference Factorsmentioning

confidence: 99%

“…The use of unreliable data is common in publications involving simulations. For example, to simulate plasma concentrations, input data was used from the different knowledgebase, including predictions from ADMET Predictor™, a module in the GastroPlus™, such as the P eff [24]. In this respect, fitting of the data was common [28,35,45,46] and could be unrealistic [46].…”

Section: Gastroplus™mentioning

confidence: 99%

In Vitro Dissolution and in Silico Modeling Shortcuts in Bioequivalence Testing

Al-Tabakha

Alomar

2020

Pharmaceutics

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Purpose: To review in vitro testing and simulation platforms that are in current use to predict in vivo performances of generic products as well as other situations to provide evidence for biowaiver and support drug formulations development. Methods: Pubmed and Google Scholar databases were used to review published literature over the past 10 years. The terms used were “simulation AND bioequivalence” and “modeling AND bioequivalence” in the title field of databases, followed by screening, and then reviewing. Results: A total of 22 research papers were reviewed. Computer simulation using software such as GastroPlus™, PK-Sim® and SimCyp® find applications in drug modeling. Considering the wide use of optimization for in silico predictions to fit observed data, a careful review of publications is required to validate the reliability of these platforms. For immediate release (IR) drug products belonging to the Biopharmaceutics Classification System (BCS) classes I and III, difference factor (ƒ1) and similarity factor (ƒ2) are calculated from the in vitro dissolution data of drug formulations to support biowaiver; however, this method can be more discriminatory and may not be useful for all dissolution profiles. Conclusions: Computer simulation platforms need to improve their mechanistic physiologically based pharmacokinetic (PBPK) modeling, and if prospectively validated within a small percentage of error from the observed clinical data, they can be valuable tools in bioequivalence (BE) testing and formulation development.

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In Silico Prediction of Plasma Concentrations of Fluconazole Capsules with Different Dissolution Profiles and Bioequivalence Study Using Population Simulation

Cited by 19 publications

References 29 publications

Comparator product issues for biowaiver implementation: the case of Fluconazole

Comparator product issues for biowaiver implementation: the case of Fluconazole

An In Vitro–In Vivo Simulation Approach for the Prediction of Bioequivalence

In Vitro Dissolution and in Silico Modeling Shortcuts in Bioequivalence Testing

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