比尼美替尼在肝功能损害患者中的药代动力学。

IF 4.6 2区 医学 Q1 PHARMACOLOGY & PHARMACY
Joseph Piscitelli, Erik Hahn, Lance Wollenberg, Renae Chavira, Laurence Del Frari, Micaela B Reddy
{"title":"比尼美替尼在肝功能损害患者中的药代动力学。","authors":"Joseph Piscitelli, Erik Hahn, Lance Wollenberg, Renae Chavira, Laurence Del Frari, Micaela B Reddy","doi":"10.1007/s40262-025-01509-0","DOIUrl":null,"url":null,"abstract":"<p><strong>Background and objective: </strong>Binimetinib is approved for multiple indications at a therapeutic dose of 45 mg twice a day (BID), in combination with encorafenib. A clinical hepatic impairment (HI) study was designed to evaluate the pharmacokinetics (PK), safety, and tolerability of a single oral dose of binimetinib in participants with mild, moderate, and severe HI compared with demographically matched healthy participants with respect to age, gender, and body weight.</p><p><strong>Methods: </strong>Participants were enrolled according to National Cancer Institute (NCI) classification criteria for hepatic function based on their total bilirubin and aspartate aminotransferase levels at screening. Participants enrolled into Group 1 (normal hepatic function) were matched to participants enrolled into Groups 2, 3, and 4 (mild, moderate, and severe HI, respectively) with respect to age, gender, and body weight. Dose-normalized PK parameters were evaluated because of a difference in doses for the severe HI group compared to the other groups, with the dose reduction due to the increased exposures observed in the moderate HI group.</p><p><strong>Results: </strong>Among 27 PK evaluable participants, changes in binimetinib dose-normalized PK parameters C<sub>max</sub>/D and AUC<sub>inf</sub>/D were minimal in participants with mild HI compared to the normal hepatic function group. Both the moderate and severe HI groups had significant changes as AUC<sub>inf</sub>/D increased by 81% and 111%, respectively, compared to the normal hepatic function group. Unbound AUC<sub>last</sub>/D for the moderate and severe HI groups increased by 280% and 248% compared to the normal hepatic function group, respectively.</p><p><strong>Conclusion: </strong>Based on these findings on total and unbound exposures, dose reductions are recommended for binimetinib in cancer patients with moderate and severe HI.</p><p><strong>Clinical trial registration: </strong>ClinicalTrials.gov NCT02050815, registered 29 January 2014.</p>","PeriodicalId":10405,"journal":{"name":"Clinical Pharmacokinetics","volume":" ","pages":""},"PeriodicalIF":4.6000,"publicationDate":"2025-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Pharmacokinetics of Binimetinib in Participants with Hepatic Impairment.\",\"authors\":\"Joseph Piscitelli, Erik Hahn, Lance Wollenberg, Renae Chavira, Laurence Del Frari, Micaela B Reddy\",\"doi\":\"10.1007/s40262-025-01509-0\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background and objective: </strong>Binimetinib is approved for multiple indications at a therapeutic dose of 45 mg twice a day (BID), in combination with encorafenib. A clinical hepatic impairment (HI) study was designed to evaluate the pharmacokinetics (PK), safety, and tolerability of a single oral dose of binimetinib in participants with mild, moderate, and severe HI compared with demographically matched healthy participants with respect to age, gender, and body weight.</p><p><strong>Methods: </strong>Participants were enrolled according to National Cancer Institute (NCI) classification criteria for hepatic function based on their total bilirubin and aspartate aminotransferase levels at screening. Participants enrolled into Group 1 (normal hepatic function) were matched to participants enrolled into Groups 2, 3, and 4 (mild, moderate, and severe HI, respectively) with respect to age, gender, and body weight. Dose-normalized PK parameters were evaluated because of a difference in doses for the severe HI group compared to the other groups, with the dose reduction due to the increased exposures observed in the moderate HI group.</p><p><strong>Results: </strong>Among 27 PK evaluable participants, changes in binimetinib dose-normalized PK parameters C<sub>max</sub>/D and AUC<sub>inf</sub>/D were minimal in participants with mild HI compared to the normal hepatic function group. Both the moderate and severe HI groups had significant changes as AUC<sub>inf</sub>/D increased by 81% and 111%, respectively, compared to the normal hepatic function group. Unbound AUC<sub>last</sub>/D for the moderate and severe HI groups increased by 280% and 248% compared to the normal hepatic function group, respectively.</p><p><strong>Conclusion: </strong>Based on these findings on total and unbound exposures, dose reductions are recommended for binimetinib in cancer patients with moderate and severe HI.</p><p><strong>Clinical trial registration: </strong>ClinicalTrials.gov NCT02050815, registered 29 January 2014.</p>\",\"PeriodicalId\":10405,\"journal\":{\"name\":\"Clinical Pharmacokinetics\",\"volume\":\" \",\"pages\":\"\"},\"PeriodicalIF\":4.6000,\"publicationDate\":\"2025-06-23\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Clinical Pharmacokinetics\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1007/s40262-025-01509-0\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"PHARMACOLOGY & PHARMACY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Clinical Pharmacokinetics","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1007/s40262-025-01509-0","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"PHARMACOLOGY & PHARMACY","Score":null,"Total":0}
引用次数: 0

摘要

背景和目的:Binimetinib已被批准用于多种适应症,治疗剂量为45 mg,每天两次(BID),与encorafenib联合使用。一项临床肝功能损害(HI)研究旨在评估轻度、中度和重度肝功能损害患者口服单剂量比尼美替尼的药代动力学(PK)、安全性和耐受性,并与年龄、性别和体重相匹配的健康受试者进行比较。方法:根据筛查时的总胆红素和天冬氨酸转氨酶水平,根据国家癌症研究所(NCI)的肝功能分类标准招募参与者。分组1(肝功能正常)与分组2、3、4(分别为轻度、中度和重度HI)在年龄、性别和体重方面相匹配。由于与其他组相比,重度HI组的剂量存在差异,因此对剂量标准化PK参数进行了评估,由于在中度HI组中观察到的暴露增加,剂量减少。结果:在27名可评估PK的参与者中,与肝功能正常组相比,轻度HI参与者的比尼美替尼剂量标准化PK参数Cmax/D和AUCinf/D的变化最小。与肝功能正常组相比,中度和重度HI组AUCinf/D分别增加了81%和111%,发生了显著变化。与肝功能正常组相比,中度和重度HI组未结合的AUClast/D分别增加280%和248%。结论:基于这些关于总暴露和非结合暴露的发现,建议在中度和重度HI癌症患者中减少比尼美替尼的剂量。临床试验注册:ClinicalTrials.gov NCT02050815,注册于2014年1月29日。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Pharmacokinetics of Binimetinib in Participants with Hepatic Impairment.

Background and objective: Binimetinib is approved for multiple indications at a therapeutic dose of 45 mg twice a day (BID), in combination with encorafenib. A clinical hepatic impairment (HI) study was designed to evaluate the pharmacokinetics (PK), safety, and tolerability of a single oral dose of binimetinib in participants with mild, moderate, and severe HI compared with demographically matched healthy participants with respect to age, gender, and body weight.

Methods: Participants were enrolled according to National Cancer Institute (NCI) classification criteria for hepatic function based on their total bilirubin and aspartate aminotransferase levels at screening. Participants enrolled into Group 1 (normal hepatic function) were matched to participants enrolled into Groups 2, 3, and 4 (mild, moderate, and severe HI, respectively) with respect to age, gender, and body weight. Dose-normalized PK parameters were evaluated because of a difference in doses for the severe HI group compared to the other groups, with the dose reduction due to the increased exposures observed in the moderate HI group.

Results: Among 27 PK evaluable participants, changes in binimetinib dose-normalized PK parameters Cmax/D and AUCinf/D were minimal in participants with mild HI compared to the normal hepatic function group. Both the moderate and severe HI groups had significant changes as AUCinf/D increased by 81% and 111%, respectively, compared to the normal hepatic function group. Unbound AUClast/D for the moderate and severe HI groups increased by 280% and 248% compared to the normal hepatic function group, respectively.

Conclusion: Based on these findings on total and unbound exposures, dose reductions are recommended for binimetinib in cancer patients with moderate and severe HI.

Clinical trial registration: ClinicalTrials.gov NCT02050815, registered 29 January 2014.

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
CiteScore
8.80
自引率
4.40%
发文量
86
审稿时长
6-12 weeks
期刊介绍: Clinical Pharmacokinetics promotes the continuing development of clinical pharmacokinetics and pharmacodynamics for the improvement of drug therapy, and for furthering postgraduate education in clinical pharmacology and therapeutics. Pharmacokinetics, the study of drug disposition in the body, is an integral part of drug development and rational use. Knowledge and application of pharmacokinetic principles leads to accelerated drug development, cost effective drug use and a reduced frequency of adverse effects and drug interactions.
×
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:604180095
Book学术官方微信