Eliglustat is a first-line oral treatment for adults with Gaucher disease type 1 who have cytochrome P450 (CYP) 2D6 extensive, intermediate, or poor metabolizer phenotypes. Per International Conference on Harmonisation (ICH) E14 guidance, a Phase 1 Thorough Electrocardiographic (ECG) Study was done during drug development to assess eliglustat's effects on cardiac repolarization by measuring ECG intervals in healthy adult subjects. Using data from the Thorough ECG study, we performed pharmacokinetic/pharmacodynamic-ECG modeling to establish the relationship between eliglustat concentrations and their effects on ECG intervals. We then used that concentration-response relationship to predict the effects of eliglustat on each ECG interval for each CYP2D6 metabolizer phenotype (the main determinant of eliglustat exposure) and in different, drug-drug interaction scenarios. These predictions, together with other exposure-related factors, contributed to the CYP2D6 phenotype-based dosing recommendations for eliglustat, including dose adjustments and contraindications when co-administered with drugs metabolized by the CYP2D6 and CYP3A pathways.

Eliglustat是一类针对Gaucher疾病1型成人的一线口服治疗，该类型的成人患有细胞色素P450（CYP）2D6广泛，中度或不良代谢者表型。根据国际协调会议（ICH）E14的指导，在药物开发过程中进行了1期彻底心电图（ECG）研究，以通过测量健康成人受试者的ECG间隔来评估eliglustat对心脏复极的影响。使用来自Thorough ECG研究的数据，我们进行了药代动力学/药效学-ECG模型，以建立eliglustat浓度与其对ECG间隔的影响之间的关系。然后，我们使用浓度-反应关系来预测eliglustat对每个CYP2D6代谢物表型（eliglustat暴露的主要决定因素）的每个ECG间隔的影响，药物相互作用的场景。这些预测以及其他与暴露相关的因素共同为依格司他的基于CYP2D6表型的给药建议做出了贡献，包括与由CYP2D6和CYP3A途径代谢的药物共同给药时的剂量调整和禁忌症。