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Physiologically Based Biopharmaceutics Modeling of Food Effect for Basmisanil: A Retrospective Case Study of the Utility for Formulation Bridging

Basmisanil, is a lipophilic drug substance, exhibiting poor solubility and good permeability (BCS class 2). A validated physiologically based biopharmaceutics model (PBBM) has been previously described for tablets dosed in the fed state. The PBBM captured the less than proportional increases in expo...

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Autores principales: Belubbi, Tejashree, Bassani, Davide, Stillhart, Cordula, Parrott, Neil
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9862143/
https://www.ncbi.nlm.nih.gov/pubmed/36678820
http://dx.doi.org/10.3390/pharmaceutics15010191
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author Belubbi, Tejashree
Bassani, Davide
Stillhart, Cordula
Parrott, Neil
author_facet Belubbi, Tejashree
Bassani, Davide
Stillhart, Cordula
Parrott, Neil
author_sort Belubbi, Tejashree
collection PubMed
description Basmisanil, is a lipophilic drug substance, exhibiting poor solubility and good permeability (BCS class 2). A validated physiologically based biopharmaceutics model (PBBM) has been previously described for tablets dosed in the fed state. The PBBM captured the less than proportional increases in exposure at higher doses well and indicated that absorption was dissolution rate-limited below 200 mg while solubility was limiting for higher doses. In this study, a model for dosing in the fasted state is described and is verified for simulation of the food effect where exposures were ~1.5 fold higher when a 660 mg tablet was given with food. The model is then applied to simulate the food effect for a granules formulation given at a lower dose (120 mg). The food effect at the lower dose was reasonably simulated with a ratio of simulated/observed food effect of 1.35 for Cmax and 0.83 for AUC. Sensitivity analysis was carried out for uncertain model parameters to confirm that the model could predict the magnitude of the positive food effect with moderate to high confidence. This study suggests that a verified PBBM can provide a useful alternative to a repeat food effect study when formulation changes are minor. However, there is need for further evaluation of the approach and a definition of what formulation changes are minor in this context. In addition, this work highlights some uncertainties in the handling of solubility in PBBM, in particular around temperature dependency of solubility and the parameterization of bile salt solubilization using measurements in biorelevant media.
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spelling pubmed-98621432023-01-22 Physiologically Based Biopharmaceutics Modeling of Food Effect for Basmisanil: A Retrospective Case Study of the Utility for Formulation Bridging Belubbi, Tejashree Bassani, Davide Stillhart, Cordula Parrott, Neil Pharmaceutics Article Basmisanil, is a lipophilic drug substance, exhibiting poor solubility and good permeability (BCS class 2). A validated physiologically based biopharmaceutics model (PBBM) has been previously described for tablets dosed in the fed state. The PBBM captured the less than proportional increases in exposure at higher doses well and indicated that absorption was dissolution rate-limited below 200 mg while solubility was limiting for higher doses. In this study, a model for dosing in the fasted state is described and is verified for simulation of the food effect where exposures were ~1.5 fold higher when a 660 mg tablet was given with food. The model is then applied to simulate the food effect for a granules formulation given at a lower dose (120 mg). The food effect at the lower dose was reasonably simulated with a ratio of simulated/observed food effect of 1.35 for Cmax and 0.83 for AUC. Sensitivity analysis was carried out for uncertain model parameters to confirm that the model could predict the magnitude of the positive food effect with moderate to high confidence. This study suggests that a verified PBBM can provide a useful alternative to a repeat food effect study when formulation changes are minor. However, there is need for further evaluation of the approach and a definition of what formulation changes are minor in this context. In addition, this work highlights some uncertainties in the handling of solubility in PBBM, in particular around temperature dependency of solubility and the parameterization of bile salt solubilization using measurements in biorelevant media. MDPI 2023-01-05 /pmc/articles/PMC9862143/ /pubmed/36678820 http://dx.doi.org/10.3390/pharmaceutics15010191 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Belubbi, Tejashree
Bassani, Davide
Stillhart, Cordula
Parrott, Neil
Physiologically Based Biopharmaceutics Modeling of Food Effect for Basmisanil: A Retrospective Case Study of the Utility for Formulation Bridging
title Physiologically Based Biopharmaceutics Modeling of Food Effect for Basmisanil: A Retrospective Case Study of the Utility for Formulation Bridging
title_full Physiologically Based Biopharmaceutics Modeling of Food Effect for Basmisanil: A Retrospective Case Study of the Utility for Formulation Bridging
title_fullStr Physiologically Based Biopharmaceutics Modeling of Food Effect for Basmisanil: A Retrospective Case Study of the Utility for Formulation Bridging
title_full_unstemmed Physiologically Based Biopharmaceutics Modeling of Food Effect for Basmisanil: A Retrospective Case Study of the Utility for Formulation Bridging
title_short Physiologically Based Biopharmaceutics Modeling of Food Effect for Basmisanil: A Retrospective Case Study of the Utility for Formulation Bridging
title_sort physiologically based biopharmaceutics modeling of food effect for basmisanil: a retrospective case study of the utility for formulation bridging
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9862143/
https://www.ncbi.nlm.nih.gov/pubmed/36678820
http://dx.doi.org/10.3390/pharmaceutics15010191
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