对中度/重度肝功能损害受试者和匹配对照受试者进行雷沙芬净的药代动力学和安全性的 I 期研究。

IF 2.9 3区 医学 Q2 PHARMACOLOGY & PHARMACY
Pharmacotherapy Pub Date : 2024-06-01 Epub Date: 2024-06-05 DOI:10.1002/phar.2943
Shawn Flanagan, Voon Ong, Thomas Marbury, Alena Jandourek, Ronak G Gandhi, Taylor Sandison
{"title":"对中度/重度肝功能损害受试者和匹配对照受试者进行雷沙芬净的药代动力学和安全性的 I 期研究。","authors":"Shawn Flanagan, Voon Ong, Thomas Marbury, Alena Jandourek, Ronak G Gandhi, Taylor Sandison","doi":"10.1002/phar.2943","DOIUrl":null,"url":null,"abstract":"<p><strong>Introduction: </strong>Rezafungin is a second-generation, once-weekly echinocandin antifungal approved for the treatment of invasive candidiasis, including candidemia. In phase II/III studies of rezafungin versus caspofungin, patients with severe hepatic impairment were excluded due to lack of caspofungin data in this population. This open-label, single-dose, phase I study evaluated the pharmacokinetics (primary objective) and safety of rezafungin in subjects with moderate or severe hepatic impairment versus matched, healthy subjects with normal hepatic function.</p><p><strong>Methods: </strong>Eight subjects each with moderate (Child-Pugh B) or severe (Child-Pugh C) hepatic impairment were matched 1:1 with healthy subjects for age, sex, and body mass index. Each subject received a single 400-mg, intravenous, 1-h infusion of rezafungin. Plasma pharmacokinetic sampling was performed at various time points through 336 h postdose. Pharmacokinetic parameters were derived by non-compartmental analysis. Safety was assessed throughout.</p><p><strong>Results: </strong>All 32 subjects received study treatment and were included in all analyses. Despite overlapping distributions of total plasma concentrations, based on geometric least-squares (LS) mean ratios, the area under the plasma concentration-time curve from time zero (prior to the start of infusion) to infinity (AUC<sub>0-∞</sub>) was 32% lower in subjects with moderate (LS mean ratio, 67.55; 90% confidence interval [CI]: 53.91, 84.65) and severe (LS mean ratio, 67.84; 90% CI: 57.49, 80.05) hepatic impairment versus matched healthy subjects. The maximum plasma concentration (C<sub>max</sub>) was 12% lower in moderate hepatic impairment and 28% lower in severe hepatic impairment groups. Linear regression showed no significant trend in the degree of hepatic impairment (based on Child-Pugh score) on AUC<sub>0-∞</sub> or C<sub>max</sub> (p > 0.05). Treatment-emergent adverse events were reported in seven subjects (21.9%; three subjects in each of the hepatic impairment groups, and one healthy subject), none of which were severe, serious, or resulted in withdrawal.</p><p><strong>Conclusions: </strong>Rezafungin is well tolerated and can be administered to patients with moderate or severe hepatic impairment without the need for dose adjustment. The modest reduction in exposures in subjects with hepatic impairment is not clinically meaningful and is unlikely to impact efficacy.</p>","PeriodicalId":20013,"journal":{"name":"Pharmacotherapy","volume":null,"pages":null},"PeriodicalIF":2.9000,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Phase I study of the pharmacokinetics and safety of rezafungin in subjects with moderate/severe hepatic impairment and matched control subjects.\",\"authors\":\"Shawn Flanagan, Voon Ong, Thomas Marbury, Alena Jandourek, Ronak G Gandhi, Taylor Sandison\",\"doi\":\"10.1002/phar.2943\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Introduction: </strong>Rezafungin is a second-generation, once-weekly echinocandin antifungal approved for the treatment of invasive candidiasis, including candidemia. In phase II/III studies of rezafungin versus caspofungin, patients with severe hepatic impairment were excluded due to lack of caspofungin data in this population. This open-label, single-dose, phase I study evaluated the pharmacokinetics (primary objective) and safety of rezafungin in subjects with moderate or severe hepatic impairment versus matched, healthy subjects with normal hepatic function.</p><p><strong>Methods: </strong>Eight subjects each with moderate (Child-Pugh B) or severe (Child-Pugh C) hepatic impairment were matched 1:1 with healthy subjects for age, sex, and body mass index. Each subject received a single 400-mg, intravenous, 1-h infusion of rezafungin. Plasma pharmacokinetic sampling was performed at various time points through 336 h postdose. Pharmacokinetic parameters were derived by non-compartmental analysis. Safety was assessed throughout.</p><p><strong>Results: </strong>All 32 subjects received study treatment and were included in all analyses. Despite overlapping distributions of total plasma concentrations, based on geometric least-squares (LS) mean ratios, the area under the plasma concentration-time curve from time zero (prior to the start of infusion) to infinity (AUC<sub>0-∞</sub>) was 32% lower in subjects with moderate (LS mean ratio, 67.55; 90% confidence interval [CI]: 53.91, 84.65) and severe (LS mean ratio, 67.84; 90% CI: 57.49, 80.05) hepatic impairment versus matched healthy subjects. The maximum plasma concentration (C<sub>max</sub>) was 12% lower in moderate hepatic impairment and 28% lower in severe hepatic impairment groups. Linear regression showed no significant trend in the degree of hepatic impairment (based on Child-Pugh score) on AUC<sub>0-∞</sub> or C<sub>max</sub> (p > 0.05). Treatment-emergent adverse events were reported in seven subjects (21.9%; three subjects in each of the hepatic impairment groups, and one healthy subject), none of which were severe, serious, or resulted in withdrawal.</p><p><strong>Conclusions: </strong>Rezafungin is well tolerated and can be administered to patients with moderate or severe hepatic impairment without the need for dose adjustment. The modest reduction in exposures in subjects with hepatic impairment is not clinically meaningful and is unlikely to impact efficacy.</p>\",\"PeriodicalId\":20013,\"journal\":{\"name\":\"Pharmacotherapy\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":2.9000,\"publicationDate\":\"2024-06-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Pharmacotherapy\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1002/phar.2943\",\"RegionNum\":3,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2024/6/5 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"Q2\",\"JCRName\":\"PHARMACOLOGY & PHARMACY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Pharmacotherapy","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1002/phar.2943","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/6/5 0:00:00","PubModel":"Epub","JCR":"Q2","JCRName":"PHARMACOLOGY & PHARMACY","Score":null,"Total":0}
引用次数: 0

摘要

简介雷沙芬净是一种第二代棘白菌素类抗真菌药物,每周用药一次,已被批准用于治疗侵袭性念珠菌病,包括念珠菌血症。在雷沙芬净与卡泊芬净的II/III期研究中,由于缺乏卡泊芬净在严重肝功能损害患者中的数据,因此排除了这类患者。这项开放标签、单剂量、I期研究评估了雷沙芬净在中度或重度肝功能损害受试者与肝功能正常的匹配健康受试者中的药代动力学(主要目标)和安全性:方法:8 名中度(Child-Pugh B)或重度(Child-Pugh C)肝功能受损的受试者与健康受试者在年龄、性别和体重指数方面进行 1:1 配对。每名受试者接受一次 400 毫克的雷沙芬净静脉注射,时间为 1 小时。在用药后 336 小时内的不同时间点进行血浆药代动力学采样。药代动力学参数通过非室分析得出。安全性评估贯穿始终:所有 32 名受试者都接受了研究治疗,并纳入了所有分析。尽管总血浆浓度的分布存在重叠,但根据几何最小二乘法(LS)平均比值,与匹配的健康受试者相比,中度(LS平均比值为67.55;90%置信区间[CI]:53.91, 84.65)和重度(LS平均比值为67.84;90%置信区间[CI]:57.49, 80.05)肝功能损害受试者从零时(输注开始前)到无穷大的血浆浓度-时间曲线下面积(AUC0-∞)低32%。中度肝功能损害组的最大血浆浓度(Cmax)比重度肝功能损害组低 12%,低 28%。线性回归结果显示,肝功能损害程度(基于 Child-Pugh 评分)对 AUC0-∞ 或 Cmax 的影响无明显趋势(p > 0.05)。7名受试者(21.9%;肝功能损害组各有3名受试者,1名健康受试者)报告了治疗突发不良事件,其中无严重不良事件或导致停药:结论:雷沙芬吉耐受性良好,可用于中度或重度肝功能损害患者,无需调整剂量。肝功能受损受试者的暴露量略有降低,但这并不具有临床意义,也不太可能影响疗效。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Phase I study of the pharmacokinetics and safety of rezafungin in subjects with moderate/severe hepatic impairment and matched control subjects.

Introduction: Rezafungin is a second-generation, once-weekly echinocandin antifungal approved for the treatment of invasive candidiasis, including candidemia. In phase II/III studies of rezafungin versus caspofungin, patients with severe hepatic impairment were excluded due to lack of caspofungin data in this population. This open-label, single-dose, phase I study evaluated the pharmacokinetics (primary objective) and safety of rezafungin in subjects with moderate or severe hepatic impairment versus matched, healthy subjects with normal hepatic function.

Methods: Eight subjects each with moderate (Child-Pugh B) or severe (Child-Pugh C) hepatic impairment were matched 1:1 with healthy subjects for age, sex, and body mass index. Each subject received a single 400-mg, intravenous, 1-h infusion of rezafungin. Plasma pharmacokinetic sampling was performed at various time points through 336 h postdose. Pharmacokinetic parameters were derived by non-compartmental analysis. Safety was assessed throughout.

Results: All 32 subjects received study treatment and were included in all analyses. Despite overlapping distributions of total plasma concentrations, based on geometric least-squares (LS) mean ratios, the area under the plasma concentration-time curve from time zero (prior to the start of infusion) to infinity (AUC0-∞) was 32% lower in subjects with moderate (LS mean ratio, 67.55; 90% confidence interval [CI]: 53.91, 84.65) and severe (LS mean ratio, 67.84; 90% CI: 57.49, 80.05) hepatic impairment versus matched healthy subjects. The maximum plasma concentration (Cmax) was 12% lower in moderate hepatic impairment and 28% lower in severe hepatic impairment groups. Linear regression showed no significant trend in the degree of hepatic impairment (based on Child-Pugh score) on AUC0-∞ or Cmax (p > 0.05). Treatment-emergent adverse events were reported in seven subjects (21.9%; three subjects in each of the hepatic impairment groups, and one healthy subject), none of which were severe, serious, or resulted in withdrawal.

Conclusions: Rezafungin is well tolerated and can be administered to patients with moderate or severe hepatic impairment without the need for dose adjustment. The modest reduction in exposures in subjects with hepatic impairment is not clinically meaningful and is unlikely to impact efficacy.

求助全文
通过发布文献求助,成功后即可免费获取论文全文。 去求助
来源期刊
Pharmacotherapy
Pharmacotherapy 医学-药学
CiteScore
7.80
自引率
2.40%
发文量
93
审稿时长
4-8 weeks
期刊介绍: Pharmacotherapy is devoted to publication of original research articles on all aspects of human pharmacology and review articles on drugs and drug therapy. The Editors and Editorial Board invite original research reports on pharmacokinetic, bioavailability, and drug interaction studies, clinical trials, investigations of specific pharmacological properties of drugs, and related topics.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术官方微信