In-vitro–in-silico investigation of the negative food effect of zolpidem when administered as immediate-release tablets
- Objectives: The main objective of the present work was to combine in vitro and in silico tools to better understand the in vivo behavior of the immediate release (IR) formulation of zolpidem in the fasted and fed states. Methods: The dissolution of zolpidem was evaluated using biorelevant media simulating the gastric and intestinal environment in the fasted and fed states. Additionally, the influence of high viscosity and high fat content on the release of zolpidem under fed state conditions was investigated. The in vitro results were combined with a physiologically based pharmacokinetic (PBPK) model constructed with Simcyp to simulate the zolpidem pharmacokinetic profile in both prandial states. Key findings: In vitro biorelevant dissolution experiments representing the fasted and fed states, combined with PBPK modelling, were able to simulate the plasma profiles from the clinical food effect studies well. Experiments reflecting the pH and fat content of the meal led to a good prediction of the zolpidem plasma profile in the fed state, whereas increasing the viscosity of the gastric media led to an under-prediction. Conclusions: This work demonstrates that the combination of biorelevant dissolution testing and PBPK modelling is very useful for understanding the in-vivo behavior of zolpidem in the fasted and fed states. This approach could be implemented in the development of other drugs exhibiting negative food effects, saving resources and bringing new drug products to the market faster.
Author: | Rafael Leal Monteiro Paraiso, Ayahisa Watanabe, Cord J. Andreas, David Turner, Patricia Zane, Jennifer B. DressmanGND |
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URN: | urn:nbn:de:hebis:30:3-546782 |
DOI: | https://doi.org/10.1111/jphp.13161 |
Parent Title (English): | Journal of Pharmacy and Pharmacology |
Publisher: | Royal Pharmaceutical Society |
Place of publication: | London |
Document Type: | Article |
Language: | English |
Year of Completion: | 2019 |
Date of first Publication: | 2019/09/30 |
Publishing Institution: | Universitätsbibliothek Johann Christian Senckenberg |
Release Date: | 2020/05/11 |
Tag: | PBPK modelling; biorelevant dissolution; food effect; in-vitro–in-vivo correlation; zolpidem |
Volume: | 71 |
Page Number: | 14 |
First Page: | 1663 |
Last Page: | 1676 |
HeBIS-PPN: | 464086361 |
Institutes: | Biochemie, Chemie und Pharmazie |
Dewey Decimal Classification: | 5 Naturwissenschaften und Mathematik / 54 Chemie / 540 Chemie und zugeordnete Wissenschaften |
Sammlungen: | Universitätspublikationen |
Licence (German): | Deutsches Urheberrecht |