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首页> 外文期刊>The Journal of Clinical Pharmacology: Official Journal of the American College of Clinical Pharmacology >Lucerastat, an Iminosugar for Substrate Reduction Therapy: Pharmacokinetics, Tolerability, and Safety in Subjects With Mild, Moderate, and Severe Renal Function Impairment
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Lucerastat, an Iminosugar for Substrate Reduction Therapy: Pharmacokinetics, Tolerability, and Safety in Subjects With Mild, Moderate, and Severe Renal Function Impairment

机译：Lucerastat，一种用于底物还原疗法的Iminosugar：具有轻度，中度和严重肾功能损伤的受试者的药代动力学，耐受性和安全性

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Lucerastat, an inhibitor of glucosylceramide synthase, has the potential for substrate reduction therapy in glycosphingolipid storage disorders such as Fabry disease. In pharmacokinetic studies in rats, dogs, and healthy subjects, the main route of elimination was renal. The pharmacokinetics, tolerability, and safety of lucerastat were evaluated in subjects with mild (group A), moderate (group B), and severe (group C) renal impairment. Group D included healthy subjects. Thirty-two subjects (8 per group) were included in this single-center, open-label study and received a single oral dose of 1000 mg lucerastat in groups A and B and 500 mg in groups C and D. The degree of renal impairment of the subjects was based on estimated glomerular filtration rate. Plasma lucerastat concentrations (dose-corrected) were higher in groups B and C compared to group D. The elimination phase half-life was slower in groups B (9.6 hours) and C (16.1 hours) compared to group D (7.0 hours). Increased exposure to lucerastat was observed in subjects from groups B and C with ratio of geometric means (90%CI) of 1.60 (1.29, 1.98) for group B vs D and 3.17 (2.76, 3.65) for group C vs D. There were no clinically relevant abnormalities in vital signs, 12-lead electrocardiograms, and clinical laboratory values. Four nonserious adverse events were reported by 4 subjects (1 in group A, 3 in group D). Lucerastat was well tolerated in all dose groups. Dose adjustment is warranted in subjects with moderate and severe renal impairment.
机译：Lucerastat是葡萄糖酰胺合成酶的抑制剂，具有糖磷脂储存障碍等底物还原治疗的可能性。在大鼠，狗和健康受试者的药代动力学研究中，消除的主要途径是肾脏。在具有轻度（A组），中等（B组）和严重（C组）肾损伤的受试者中评估荧光素的药代动力学，耐受性和安全性。组D包括健康受试者。在该单中心，开放标签研究中包含32个受试者（每组8个），并在C组和D组中接受1000mg Lucerastat的单个口服剂量为1000毫克，500mg。肾损伤程度受试者基于估计的肾小球过滤速率。与D组相比，B组和C组血浆荧光剂浓度（剂量校正）较高。与D组（7.0小时）相比，B组（9.6小时）和C（16.1小时）中的消除阶段半衰期较慢。在B组的B和C组的受试者中观察到荧光球的受试者的接触增加，GS D和3.17（2.76,3.65）的几何均值（1.29,1.98）的比例Vs D和D.在生命体征，12铅心电图和临床实验室值中没有临床相关的异常。 4个受试者报告了四次非令人遗憾的不良事件（A组，D组中的1分）。 Lucerastat在所有剂量基团中耐受良好。剂量调整在受中度和严重肾脏损伤的主题中有保证。

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