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首页> 外文期刊>The Journal of Clinical Pharmacology: Official Journal of the American College of Clinical Pharmacology >Pharmacokinetics and safety of galantamine in subjects with hepatic impairment and healthy volunteers.
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Pharmacokinetics and safety of galantamine in subjects with hepatic impairment and healthy volunteers.

机译：加兰他敏在肝功能不全受试者和健康志愿者中的药代动力学和安全性。

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The objective of this study was to compare the pharmacokinetics and safety of galantamine in subjects with hepatic impairment with those in healthy subjects. This was an open-label study in which a single oral 4-mg dose of galantamine was administered to volunteers with mild (Child-Pugh score of 5-6, n = 8), moderate (Child-Pugh score of 7-9, n = 8), or severe hepatic impairment (Child-Pugh score of 10-15, n = 1) and to healthy, matched control subjects (n = 8). Galantamine pharmacokinetics and safety (adverse events, laboratory test results, electrocardiograms, vital signs, and cardiac events) were assessed over 6 days after administration of galantamine. The pharmacokinetic parameters of galantamine were similar in subjects with mild hepatic impairment compared with healthy controls. Compared with the healthy control group, subjects with moderate hepatic impairment showed relative increases in the area under the plasma-concentration curve from zero to infinity (AUC0-infinity) (+33%) and terminal half-life (t1/2) (+30%) (p = 0.051 and p = 0.003, respectively), a 23% relative decrease in total plasma clearance (p = 0.061), and a small but significant relative increase in the fraction of free plasma galantamine (p = 0.009). Galantamine was well tolerated by all subjects. There were no serious adverse events (AEs) or premature withdrawals from the study because of AEs. Reported AEs were headache (three cases), nausea (one case), and paresthesia (one case). There were no clinically relevant changes in clinical laboratory findings, vital signs, and electrocardiograms. Low patient recruitment (n = 1) precluded statistical analysis of galantamine pharmacokinetics and safety in severe hepatic impairment. It was concluded that the pharmacokinetics of galantamine in subjects with mild hepatic impairment was similarto those in healthy subjects. In subjects with moderate hepatic impairment, galantamine clearance was decreased by approximately 23% compared with normal volunteers. Galantamine was also well tolerated and appeared to be safe in subjects with mild ormoderate hepatic impairment. Based on the study results, it appears that it would not be necessary to adjust doses of galantamine during administration to subjects with mild hepatic impairment. In subjects with moderately impaired hepatic function, dose titration should proceed cautiously. Unfortunately, difficulties with patient recruitment did not allow adequate assessment of the safety of galantamine in subjects with severe hepatic impairment in this study. Therefore, the use of galantamine in subjects with severe hepatic impairment is not recommended.
机译：这项研究的目的是比较加兰他敏在肝功能不全患者和健康人群中的药代动力学和安全性。这是一项开放标签研究，其中向中度（Child-Pugh评分为5-6，n = 8），中度（Child-Pugh评分为7-9， n = 8）或严重肝功能不全（Child-Pugh评分为10-15，n = 1），以及健康，匹配的对照组（n = 8）。加兰他敏给药后6天内评估了加兰他敏的药代动力学和安全性（不良事件，实验室测试结果，心电图，生命体征和心脏事件）。与健康对照组相比，轻度肝功能不全受试者的加兰他敏药代动力学参数相似。与健康对照组相比，中度肝功能不全的受试者血浆浓度曲线下的面积相对增加，从零到无穷大（AUC0-无穷大）（+ 33％）和终末半衰期（t1 / 2）（+ 30％）（分别为p = 0.051和p = 0.003），总血浆清除率相对降低23％（p = 0.061），以及游离血浆加兰他敏的比例有小幅但显着的相对增加（p = 0.009）。加兰他敏对所有受试者均耐受良好。没有因不良事件而导致的严重不良事件（AE）或从研究中退出。报告的不良事件为头痛（3例），恶心（1例）和感觉异常（1例）。临床实验室检查结果，生命体征和心电图无临床相关变化。低的患者招募（n = 1）排除了加兰他敏药代动力学和严重肝功能不全安全性的统计分析。结论是加兰他敏在轻度肝功能不全受试者中的药代动力学与健康受试者相似。与正常志愿者相比，中度肝功能不全患者的加兰他敏清除率降低了约23％。加兰他敏也具有良好的耐受性，对于轻度或中度肝功能不全的受试者似乎是安全的。根据研究结果，似乎没有必要在轻度肝功能不全的受试者服用期间调整加兰他敏的剂量。在中度肝功能受损的受试者中，应谨慎进行剂量滴定。不幸的是，在这项研究中，患者招募的困难无法充分评估加兰他敏在患有严重肝功能不全的受试者中的安全性。因此，不建议在严重肝功能不全的受试者中使用加兰他敏。

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