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

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).