Introduction to the OrBiTo decision tree to select the most appropriate in vitro methodology for release testing of solid oral dosage forms during development

Andreas, Cord J.; Rosenberger, Julian; Butler, James; Augustijns, Patrick; McAllister, Mark; Abrahamsson, Bertil; Dressman, Jennifer B.

doi:10.1016/j.ejpb.2018.07.003

Cited by 31 publications

(13 citation statements)

References 38 publications

(21 reference statements)

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“…This in vitro dissolution method could be of application for other non-complex immediate release candesartan cilexetil formulations. Complex formulations with lipids for which digestion by intestinal enzymes could affect release or polymer formulations, which could help supersaturation processes may need a different in vitro dissolution method [17,37].…”

Section: Discussionmentioning

confidence: 99%

“…Prediction of plasma levels using as input in vitro dissolution results could be done with other commercial PBPK modelling packages [15,16], but we intended to develop a method that could be easily implemented in basic modelling software or even with excel worksheets. Regarding the design of the dissolution method, we checked the standard conditions already published for candesartan and explore the suggested alternatives in recent reports about biorelevant dissolution conditions selection based on the biopharmaceutical properties of the drug [17,18].…”

Section: Introductionmentioning

confidence: 99%

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Candesartan Cilexetil In Vitro–In Vivo Correlation: Predictive Dissolution as a Development Tool

et al. 2020

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The main objective of this investigation was to develop an in vitro–in vivo correlation (IVIVC) for immediate release candesartan cilexetil formulations by designing an in vitro dissolution test to be used as development tool. The IVIVC could be used to reduce failures in future bioequivalence studies. Data from two bioequivalence studies were scaled and combined to obtain the dataset for the IVIVC. Two-step and one-step approaches were used to develop the IVIVC. Experimental solubility and permeability data confirmed candesartan cilexetil. Biopharmaceutic Classification System (BCS) class II candesartan average plasma profiles were deconvoluted by the Loo-Riegelman method to obtain the oral fractions absorbed. Fractions dissolved were obtained in several conditions in USP II and IV apparatus and the results were compared calculating the f2 similarity factor. Levy plot was constructed to estimate the time scaling factor and to make both processes, dissolution and absorption, superimposable. The in vitro dissolution experiment that reflected more accurately the in vivo behavior of the products of candesartan cilexetil employed the USP IV apparatus and a three-step pH buffer change, from 1.2 to 4.5 and 6.8, with 0.2% of Tween 20. This new model was able to predict the in vivo differences in dissolution and it could be used as a risk-analysis tool for formulation selection in future bioequivalence trials.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Candesartan Cilexetil In Vitro–In Vivo Correlation: Predictive Dissolution as a Development Tool

et al. 2020

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“…Regulatory agencies have shown interest in better understanding the simulation platforms' reliability in dossier applications with consistency in reporting [73]. In 2012, the European Union (EU) initiated work packages under the project oral biopharmaceutics tools (OrBiTo) to improve oral absorption prediction tools based on formulation variables [74]. The FDA internal research initiatives included a potential grant for the development of a virtual bioequivalence trial simulation platform that integrates population pharmacokinetic modeling algorithms into PBPK models [75].…”

Section: Other In Silico Platformsmentioning

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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“…Based on the outcomes from each work package, an intensive data analysis was performed and a decision tree was developed for different kinds of formulations and compounds of interest (e.g., immediate-release formulation for a weakly basic compound). The decision tree will assist formulation scientists in selecting the most appropriate in vitro dissolution test (eventually coupled with computational modeling) to better understand what can be expected from this formulation (in terms of systemic exposure) if it would be given to patients in the later stage of drug development (10). The decision tree can be downloaded from the following website: www.orbito-dissolution.eu.…”

Section: Introductionmentioning

confidence: 99%

Leveraging Oral Drug Development to a Next Level: Impact of the IMI-Funded OrBiTo Project on Patient Healthcare

et al. 2021

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A thorough understanding of the behavior of drug formulations in the human gastrointestinal (GI) tract is essential when working in the field of oral drug development in a pharmaceutical company. For orally administered drug products, various GI processes, including disintegration of the drug formulation, drugrelease, dissolution, precipitation, degradation, dosage form transit and permeation, dictate absorption into the systemic circulation. These processes are not always fully captured in predictive in vitro and in silico tools, as commonly applied in the pre-clinical stage of formulation drug development. A collaborative initiative focused on the science of oral biopharmaceutics was established in 2012 between academic institutions and industrial companies to innovate, optimize and validate these in vitro and in silico biopharmaceutical tools. From that perspective, the predictive power of these models can be revised and, if necessary, optimized to improve the accuracy toward predictions of the in vivo performance of orally administered drug products in patients. The IMI/EFPIA-funded “Oral Bioavailability Tools (OrBiTo)” project aimed to improve our fundamental understanding of the GI absorption process. The gathered information was integrated into the development of new (or already existing) laboratory tests and computer-based methods in order to deliver more accurate predictions of drug product behavior in a real-life setting. These methods were validated with the use of industrial data. Crucially, the ultimate goal of the project was to set up a scientific framework (i.e., decision trees) to guide the use of these new tools in drug development. The project aimed to facilitate and accelerate the formulation development process and to significantly reduce the need for animal experiments in this area as well as for human clinical studies in the future. With respect to the positive outcome for patients, high-quality oral medicines will be developed where the required dose is well-calculated and consistently provides an optimal clinical effect. In a first step, this manuscript summarizes the setup of the project and how data were collected across the different work packages. In a second step, case studies of how this project contributed to improved knowledge of oral drug delivery which can be used to develop improved products for patients will be illustrated.

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Introduction to the OrBiTo decision tree to select the most appropriate in vitro methodology for release testing of solid oral dosage forms during development

Cited by 31 publications

References 38 publications

Candesartan Cilexetil In Vitro–In Vivo Correlation: Predictive Dissolution as a Development Tool

Candesartan Cilexetil In Vitro–In Vivo Correlation: Predictive Dissolution as a Development Tool

In Vitro Dissolution and in Silico Modeling Shortcuts in Bioequivalence Testing

Leveraging Oral Drug Development to a Next Level: Impact of the IMI-Funded OrBiTo Project on Patient Healthcare

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