Eliglustat and cardiac comorbidities in Gaucher disease: a pharmacogenomic approach to safety and efficacy

作者：Noor Ul Ain, Armaan Saith, Audrey Ruan, Ruhua Yang, Aaron S. Burton, Pramod K. Mistry · 发表于：Frontiers in Medicine · 年份：2025 · DOI：10.3389/fmed.2025.1535099 · 被引用次数：5 · 研究领域：Lysosomal Storage Disorders Research、Calcium signaling and nucleotide metabolism、Trypanosoma species research and implications

Introduction Gaucher disease (GD), a lysosomal storage disorder, results from the accumulation of glycosphingolipids due to deficient lysosomal glucocerebrosidase activity. This pathological accumulation triggers immune activation, which paradoxically induces UDPglucose ceramide glucosyltransferase (UGCG), further exacerbating the metabolic defect. Eliglustat, a highly specific inhibitor of UGCG, functions as a substrate reduction therapy (SRT) and has demonstrated efficacy in reversing GD manifestations in clinical trials and real-world settings. Despite its established safety profile, preclinical studies have shown that supratherapeutic concentrations of eliglustat can inhibit ion channels involved in cardiac electrophysiology. However, pharmacogenomic-guided dosing ensures therapeutic efficacy while maintaining a wide safety margin, minimizing such risks. Nevertheless, lingering concerns regarding cardiac safety have persisted, particularly in patients with preexisting cardiac comorbidities. Methods We report a single-center experience of eliglustat use in 13 patients with type 1 Gaucher disease (GD1) and concurrent cardiac comorbidities. Patients underwent standard cardiac evaluations, including electrocardiogram (EKG) with QTc interval assessment and echocardiogram. Eliglustat dosing was guided by CYP2D6 metabolizer status, and potential drug–drug interactions (DDIs) were carefully monitored. Results Cardiac comorbidities included prior myocardial infarction ( n = 2), ao...