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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.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods<\/jats:title>\n            <jats:p>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.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results<\/jats:title>\n            <jats:p>We simulated, using popPK data, oral and intravenous dosing regimens resulting in adequate target exposure in\u2009&gt;\u200990% 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.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p>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).<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Graphical abstract<\/jats:title>\n          <\/jats:sec>","DOI":"10.1007\/s00467-025-06688-3","type":"journal-article","created":{"date-parts":[[2025,2,3]],"date-time":"2025-02-03T23:29:06Z","timestamp":1738625346000},"page":"2009-2019","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Model-informed repurposing of eliglustat for treatment and prophylaxis of Shiga toxin-producing Escherichia coli hemolytic-uremic syndrome (STEC-HUS) in children"],"prefix":"10.1007","volume":"40","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2152-4490","authenticated-orcid":false,"given":"David F. G. 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Instead, it utilizes randomly generated patient data to simulate clinical scenarios. The creation and use of these randomly generated datasets were conducted in accordance with ethical research guidelines, ensuring that no actual patient information was utilized. As the study does not involve human participants or identifiable data, ethical approval from an institutional review board (IRB) or ethics committee was not required. However, all procedures followed applicable ethical standards for the use of simulated data in research.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval"}},{"value":"Nicole van der Kar has no conflicts of interest related to this study, but is the chair of the Thrombotic Microangiopathy Working Group of ERKnet (unpaid) and the chair of the International Steering Committee symposia on Verocytotoxin-Producing E. coli Infections (unpaid). She also receives consulting fees from Roche and Alexion (to institution), payment for lectures from Sobi (to institution), and fees for expert testimony from Samsung (to institution). Reena V. Kartha has received investigator-initiated grants from Sanofi, Pfizer Inc., and Takeda Pharmaceuticals for research in Gaucher disease, and receives consulting fees from Gain Therapeutics, payment for lectures from Saterdalen & Associates LLC, and support for attending meetings from Saterdalen & Associates LLC. She is also a member of several advisory boards and boards related to rare diseases. Saskia N. de Wildt has received research grants from EU IMI2, Roche (investigator-initiated research grant), and the Bill & Melinda Gates Foundation. She also receives payment for expert testimony from Erasmus MC University Medical Center (to institution), and holds a pending patent for the use of PENK as an AKI marker in children. She is also involved in several non-commercial and commercial foundations and organizations.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}