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A Combined In-Vitro and GastroPlus® Modeling to Study the Effect of Intestinal Precipitation on Cinnarizine Plasma Profile in a Fasted State

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Abstract

Poorly water-soluble weak base molecules such as cinnarizine often exhibit pH-dependent solubility within the gastrointestinal tract. This means that their solubility can be influenced by the pH of the surrounding environment, and this can affect their oral absorption. The differential pH solubility between the fasted-state stomach and intestine is an important consideration when studying the oral absorption of cinnarizine. Cinnarizine has moderate permeability and is known to exhibit supersaturation and precipitation in fasted-state simulated intestinal fluid (FaSSIF), which can significantly impact its oral absorption. The present work is aimed at studying the precipitation behavior of cinnarizine in FaSSIF using biorelevant in vitro tools and GastroPlus® modeling, to identify the factors contributing to the observed variability in clinical plasma profiles. The study found that cinnarizine demonstrated variable precipitation rates under different bile salt concentrations, which could impact the concentration of the drug available for absorption. The results also showed that a precipitation-integrated modeling approach accurately predicted the mean plasma profiles from the clinical studies. The study concluded that intestinal precipitation may be one of the factors contributing to the observed variability in Cmax but not the AUC of cinnarizine. The study further suggests that the integration of experimental precipitation results representing a wider range of FaSSIF conditions would increase the probability of predicting some of the observed variability in clinical results. This is important for biopharmaceutics scientists, as it can help them evaluate the risk of in vivo precipitation impacting drug and/or drug product performance.

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Data Availability

All data is available upon request from the corresponding author.

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Acknowledgements

The authors would like to thank Ms. Aditi Panchal, Dr. David Harris, and Dr. Marta Venczel for their input, assistance, and support of the work in this manuscript.

Funding

All presented work in this manuscript was performed internally and supported by Sanofi US.

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  1. US Early Development Biopharmacy, Synthetics Platform, Sanofi, 350 Water Street, MA, 02141, Cambridge, USA

    Siddharth S. Kesharwani & Fady Ibrahim

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  1. Siddharth S. Kesharwani
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  2. Fady Ibrahim
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Conceptualization, data curation, formal analysis, writing (original draft, review, and editing): Siddharth Kesharwani and Fady Ibrahim.

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Correspondence to Fady Ibrahim.

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Kesharwani, S.S., Ibrahim, F. A Combined In-Vitro and GastroPlus® Modeling to Study the Effect of Intestinal Precipitation on Cinnarizine Plasma Profile in a Fasted State. AAPS PharmSciTech 24, 121 (2023). https://doi.org/10.1208/s12249-023-02577-w

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