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首页> 外文期刊>The Journal of Clinical Pharmacology: Official Journal of the American College of Clinical Pharmacology >Effect of Renal Function Impairment on the Pharmacokinetics, Safety, and Tolerability of the Iminosugar Sinbaglustat
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Effect of Renal Function Impairment on the Pharmacokinetics, Safety, and Tolerability of the Iminosugar Sinbaglustat

机译：肾功能损害对Iminoolugar Sinbaglustat的药代动力学，安全性和耐受性的影响

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摘要

Sinbaglustat (ACT-519276), a brain-penetrating inhibitor of glucosylceramide synthase and nonlysosomal glucosylceramidase, is developed as a new therapy for lysosomal storage disorders. In the first-in-human study, sinbaglustat was primarily excreted unchanged in urine. This study was conducted to evaluate the effect of mild, moderate, and severe renal function impairment on the safety, tolerability, and pharmacokinetics (PK) of sinbaglustat. In this single-center, open-label study, 32 subjects (8 per renal function group, assessed by the Cockcroft-Gault formula, and 8 healthy subjects) received a single oral dose of 200 mg sinbaglustat. Plasma PK parameters of sinbaglustat were derived by noncompartmental analysis. Standard safety and tolerability evaluations were analyzed descriptively. When compared with healthy subjects, C-max did not present clinically relevant differences in subjects with impaired renal function, but median t(max) was slightly longer in subjects with moderate and severe renal function impairment. Overall, when compared with healthy subjects, exposure to sinbaglustat based on AUC(0-t) (geometric mean and 90% confidence interval) increased in subjects with mild, moderate, and severe renal function impairment by 1.2-fold (1.08- to 1.36-fold), 1.8-fold (1.47- to 2.17-fold), and 2.6-fold (2.23- to 3.00-fold), respectively. There were no clinically relevant findings on electrocardiogram, vital signs, and clinical laboratory variables. Headache was reported by 2 of 24 subjects with renal function impairment and by 2 of 8 healthy subjects. In conclusion, 200 mg of sinbaglustat was well tolerated in all groups. In future studies, a 2- and 3-fold dose reduction is needed for subjects with moderate and severe renal function impairment, respectively.
机译：Sinbaglustat（ACT-519276）是葡萄糖神经酰胺合成酶和非溶酶体葡萄糖神经酰胺酶的脑穿透抑制剂，是一种治疗溶酶体储存障碍的新疗法。在人类的第一项研究中，sinbaglustat主要通过尿液排泄。本研究旨在评估轻度、中度和重度肾功能损害对sinbaglustat的安全性、耐受性和药代动力学（PK）的影响。在这项单中心开放标签研究中，32名受试者（按Cockcroft-Gault公式评估，每个肾功能组8名，以及8名健康受试者）单次口服200mg sinbaglustat。通过非部分分析得出sinbaglustat的血浆PK参数。对标准安全性和耐受性评估进行描述性分析。与健康受试者相比，肾功能受损受试者的C-max没有临床相关性差异，但中重度肾功能受损受试者的中位数t（max）稍长。总的来说，与健康受试者相比，在轻度、中度和重度肾功能损害受试者中，基于AUC（0-t）（几何平均值和90%置信区间）的辛巴格司他暴露量分别增加了1.2倍（1.08-1.36倍）、1.8倍（1.47-2.17倍）和2.6倍（2.23-3.00倍）。在心电图、生命体征和临床实验室变量方面没有临床相关的发现。24名肾功能受损受试者中有2名出现头痛，8名健康受试者中有2名出现头痛。总之，所有组均能耐受200mg sinbaglustat。在未来的研究中，中度和重度肾功能损害的受试者需要分别减少2倍和3倍的剂量。

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