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Open Access 03-02-2025 | Pharmacokinetics | Original Article

Model-informed repurposing of eliglustat for treatment and prophylaxis of Shiga toxin-producing Escherichia coli hemolytic-uremic syndrome (STEC-HUS) in children

Authors: David F. G. J. Wolthuis, Jolien J. M. Freriksen, Mendy ter Avest, Reena V. Kartha, Saskia N. de Wildt, Kioa Wijnsma, Nicole C. A. J. van de Kar, Rob ter Heine

Published in: Pediatric Nephrology

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Abstract

Background

Shiga toxin-producing Escherichia coli hemolytic-uremic syndrome (STEC-HUS) is a severe illness predominantly affecting young children, with limited treatment options beyond supportive care. Eliglustat, approved for Gaucher disease, shows potential in reducing Shiga toxin binding to target glomerular endothelial cells in vitro, prompting interest as a treatment for STEC-HUS. However, it remains unknown what dose is likely to be effective and safe for treatment of STEC-HUS in the pediatric population. We hypothesize that effective and safe levels of eliglustat can be reached in children.

Methods

We identified pharmacokinetic targets of efficacy for treatment and prophylaxis of STEC-HUS based on a preclinical model and human cardiac safety data. Then, we developed oral and intravenous dosing regimens using population pharmacokinetic (popPK) simulations based on an existing model enriched to allow extrapolation to a simulated virtual pediatric population. These dosing regimens were then confirmed using a verified physiologically based pharmacokinetic (PBPK) model.

Results

We simulated, using popPK data, oral and intravenous dosing regimens resulting in adequate target exposure in > 90% of all patients, with minimal expected risk for cardiotoxicity. Confirmation of these dosing regimens with PBPK modeling resulted in very similar exposure, with lower interindividual variability and minimal toxicity potential.

Conclusions

Based on pharmacokinetic modeling, we developed oral and intravenous eliglustat dosing regimens that are likely safe and effective for treatment of STEC-HUS and prophylaxis in case of outbreaks of STEC infections. Clinical evaluation of these dosing regimens in children suspected of or diagnosed with STEC-HUS is required and should include assessment of pharmacokinetics, efficacy, and safety (e.g., ECG monitoring).

Graphical abstract

Appendix
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Metadata
Title
Model-informed repurposing of eliglustat for treatment and prophylaxis of Shiga toxin-producing Escherichia coli hemolytic-uremic syndrome (STEC-HUS) in children
Authors
David F. G. J. Wolthuis
Jolien J. M. Freriksen
Mendy ter Avest
Reena V. Kartha
Saskia N. de Wildt
Kioa Wijnsma
Nicole C. A. J. van de Kar
Rob ter Heine
Publication date
03-02-2025
Publisher
Springer Berlin Heidelberg
Published in
Pediatric Nephrology
Print ISSN: 0931-041X
Electronic ISSN: 1432-198X
DOI
https://doi.org/10.1007/s00467-025-06688-3

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