540 Chemie und zugeordnete Wissenschaften
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- PBPK (1)
- PBPK modelling (1)
- amorphous solid dispersions (1)
- biorelevant dissolution (1)
- bio‐enabling formulations (1)
- etravirine (1)
- food effect (1)
- in-vitro–in-vivo correlation (1)
- modeling and simulation (1)
- zolpidem (1)
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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.
Introduction: In the development of bio-enabling formulations, innovative in vivo predictive tools to understand and predict the in vivo performance of such formulations are needed. Etravirine, a non-nucleoside reverse transcriptase inhibitor, is currently marketed as an amorphous solid dispersion (Intelence® tablets). The aims of this study were 1) to investigate and discuss the advantages of using biorelevant in vitro setups in simulating the in vivo performance of Intelence® 100 mg and 200 mg tablets, in the fed state, 2) to build a Physiologically Based Pharmacokinetic (PBPK) model by combining experimental data and literature information with the commercially available in silico software Simcyp® Simulator V17.1 (Certara UK Ltd.), and 3) to discuss the challenges when predicting the in vivo performance of an amorphous solid dispersion and identify the parameters which influence the pharmacokinetics of etravirine most.
Methods: Solubility, dissolution and transfer experiments were performed in various biorelevant media simulating the fasted and fed state environment in the gastrointestinal tract. An in silico PBPK model for healthy volunteers was developed in the Simcyp® Simulator, using in vitro results and data available from the literature as input. The impact of pre- and post-absorptive parameters on the pharmacokinetics of etravirine was investigated using simulations of various scenarios.
Results: In vitro experiments indicated a large effect of naturally occurring solubilizing agents on the solubility of etravirine. Interestingly, supersaturated concentrations of etravirine were observed over the entire duration of dissolution experiments on Intelence® tablets. Coupling the in vitro results with the PBPK model provided the opportunity to investigate two possible absorption scenarios, i.e. with or without implementation of precipitation. The results from the simulations suggested that a scenario in which etravirine does not precipitate is more representative of the in vivo data. On the post-absorptive side, it appears that the concentration dependency of the unbound fraction of etravirine in plasma has a significant effect on etravirine pharmacokinetics.
Conclusions: The present study underlines the importance of combining in vitro and in silico biopharmaceutical tools to advance our knowledge in the field of bio-enabling formulations. Future studies on other bio-enabling formulations can be used to further explore this approach to support rational formulation design as well as robust prediction of clinical outcomes.