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Modeling of the effect of cerebrospinal fluid flow modulation on locally delivered drugs in the brain

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Abstract

Cerebrospinal fluid (CSF) plays a vital role in maintaining brain homeostasis and recent research has focused on elucidating the role that convective flow of CSF plays in brain health. This paper describes a computational compartmental model of how CSF dynamics affect drug pharmacokinetics in the rat brain. Our model implements a local, sustained release approach for drug delivery to the brain. Simulation outputs highlight the potential for modulating CSF flow to improve overall drug pharmacokinetics in the central nervous system and suggest that concomitant CSF modulation and optimized drug release rates from implantable depots can be used to engineer the duration of action of chemotherapeutics. As an example, the tissue exposure of temozolomide, the standard of care treatment for glioblastoma, was modeled in conjunction with two CSF-modulating drugs: acetazolamide and verapamil. Simulations indicate that temozolomide exposure in the interstitial fluid is increased by 25% when using local sustained release delivery systems and concomitant acetazolamide delivery to reduce CSF production. This computational model can be used to produce insight on how to appropriately modulate CSF production and engineer drug release to tailor drug exposure in the brain while limiting off-target effects. As new research continues to elucidate the dynamic roles of CSF, this model can be further improved and leveraged to provide information on how CSF modulation may play a beneficial role in treating a wide variety of neurological disease.

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Code availability

MATLAB source code is available for download through the Rutgers University Libraries Repository at the following link: https://doi.org/10.7282/00000213

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Acknowledgements

This work was supported by grants from the National Institutes of Health: National Institute of Biomedical Imaging and Bioengineering (R00 EB016690) and National Institute of General Medical Sciences (T32 GM008339).

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Authors and Affiliations

  1. Department of Biomedical Engineering, Rutgers, The State University of New Jersey, New Brunswick, USA

    Caroline M. Wood, Veronica E. Farag & Jay C. Sy

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  3. Jay C. Sy
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Contributions

Conceptualization: JCS, CMW. Data curation: CMW. Formal Analysis: CMW, VEF. Funding acquisition: JCS. Investigation: JCS, VEF, CMW. Methodology: CW, JCS. Project administration: JCS, CMW. Resources: JCS, CMW. Software: CMW, VEF. Supervision: JCS. Validation: JCS, CMW. Visualization: CMW, VEF. Writing—original draft: CMW. Writing—review & editing: JCS, CMW, VEF.

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Correspondence to Jay C. Sy.

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Wood, C.M., Farag, V.E. & Sy, J.C. Modeling of the effect of cerebrospinal fluid flow modulation on locally delivered drugs in the brain. J Pharmacokinet Pharmacodyn 49, 657–671 (2022). https://doi.org/10.1007/s10928-022-09827-7

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