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An In Vitro-In Vivo Simulation Approach for the Prediction of Bioequivalence.

ABSTRACT: 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.

SUBMITTER: Vlachou M

PROVIDER: S-EPMC7865526 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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An In Vitro-In Vivo Simulation Approach for the Prediction of Bioequivalence.

Vlachou Marilena M Karalis Vangelis V

Materials (Basel, Switzerland) 20210124 3

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, an ...[more]

PMID: 33498960

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Project description:The use of in vitro human skin permeation tests is of value when addressing the quality and equivalence of topical drug products in Europe and the US. Human skin is the membrane of choice for these studies. The use of human skin as a membrane is hindered by limited access, high variability of results, and limited applicability for drugs with low skin permeability. Reconstructed human epidermis (RhE) models are validated as skin surrogates for safety tests and have been explored for percutaneous absorption testing. Clotrimazole poorly permeates human skin and is widely available for topical treatments. In this study, clotrimazole creams were used to test the ability of RhE to be used as biological membrane for bioequivalence testing, based on the Draft Guideline on Quality and Equivalence of Topical Products (CHMP/QWP/708282/2018) using a discriminative and modified in vitro permeation test (IVPT). To fulfill the validation of a discriminatory method, Canesten® 10 mg/g cream was compared with a test product with the same drug strength, along with two "negative controls" dosed at a 50% and 200% drug strength. Products were compared in finite dose conditions, regarding maximal flux (Jmax) and the total amount of drug permeated (Atotal). The results showed the discriminatory power of the method among the three drug strengths with no interference of the placebo formulation. The study design and validation complied with the requirements established in the guideline for a valid IVPT. This new test system allowed for the equivalence comparison between test and comparator product. Higher permeability of the RhE compared to human skin could be observed. This arose as a strength of the model for this modified IVPT bioequivalence testing, since comparing permeation profiles among products is envisaged instead of drawing absolute conclusions on skin permeation extent. These results may support the acceptance of RhE as biological membranes for modified IVPT in bioequivalence testing of topical products.

Project description:Tooth wear may be described as a side-effect of occlusal forces that may be further induced by the common use of contemporary prosthetic materials in practice. The purpose of this systematic review was to appraise existing evidence on enamel wear from both in vitro and clinical research and explore whether evidence from these study designs lies on the same direction. Five databases of published and unpublished research were searched without limitations in August 2019 and study selection criteria included in vitro and clinical research on enamel tooth wear. Study selection, data extraction, and risk of bias assessment were done independently and in duplicate. Random effects meta-analyses of standardized mean differences (SMDs) or weighted mean differences (WMDs) with 95% confidence intervals (CIs) were conducted while a Monte Carlo permutation test for meta-regression on the exploration of the effect of the study design on the reported outcomes was planned. A total of 27 studies (23 in vitro and 4 clinical) were eligible while 12 contributed to meta-analyses. Overall, some concerns were raised for the quality of the existing evidence and the potential for risk of bias. Enamel wear (mm) of antagonist teeth was more pronounced when opposed to conventional porcelain compared to machinable ceramics (SMD = 2.18; 95%CIs: 1.34, 3.02; p < 0.001). Polished zirconia resulted in decreased volumetric enamel wear (mm3) of opposing teeth compared to pure natural enamel (SMD = -1.06; 95%CIs: -1.73, -0.39; p = 0.002). Monolithic zirconia showed evidence of enhanced potential for antagonist wear (?m) compared to natural teeth (WMD = 107.38; 95%CIs: 30.46, 184.30; p = 0.01). Study design did not reveal an effect on the tooth wear outcome for the latter comparison when both clinical and in vitro studies were considered (three studies; Monte Carlo test, p = 0.66). In conclusion, there is an overriding need for additional evidence from clinical research to substantiate the findings from the already existing laboratory simulation studies.

Dataset Information

An In Vitro-In Vivo Simulation Approach for the Prediction of Bioequivalence.

Publications

An In Vitro-In Vivo Simulation Approach for the Prediction of Bioequivalence.

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