Pharmacokinetics of the Novel Nonsteroidal Mineralocorticoid Receptor Antagonist Ocedurenone (KBP-5074) in Individuals with Moderate Hepatic Impairment.

IF 1.9 4区 医学 Q3 PHARMACOLOGY & PHARMACY
James McCabe, Jay Zhang, Fred Yang, Vincent Benn
{"title":"Pharmacokinetics of the Novel Nonsteroidal Mineralocorticoid Receptor Antagonist Ocedurenone (KBP-5074) in Individuals with Moderate Hepatic Impairment.","authors":"James McCabe, Jay Zhang, Fred Yang, Vincent Benn","doi":"10.1007/s13318-024-00879-3","DOIUrl":null,"url":null,"abstract":"<p><strong>Background and objectives: </strong>Ocedurenone (KBP-5074) is a novel nonsteroidal mineralocorticoid receptor antagonist that has demonstrated safety and efficacy in clinical trials in patients with uncontrolled hypertension and stage 3b/4 chronic kidney disease. The aim of this study was to assess the pharmacokinetics, safety, and tolerability of ocedurenone in individuals with moderate hepatic impairment.</p><p><strong>Methods: </strong>This study was an open-label, nonrandomized, multi-center study investigating the pharmacokinetics, safety, and tolerability of a single dose of 0.5 mg ocedurenone administered orally in male and female subjects with moderate hepatic impairment (Child-Pugh B, score 7-9) compared with subjects with normal hepatic function. Serial blood samples were obtained from predose through 264 h postdose for analysis of ocedurenone concentrations using a validated liquid chromatography-tandem mass spectrometry method. Free ocedurenone concentrations in plasma were determined ex vivo using equilibrium dialysis.</p><p><strong>Results: </strong>Following a single oral dose of 0.5 mg ocedurenone administered to subjects with moderate hepatic impairment and subjects with normal hepatic function, ocedurenone was steadily absorbed with median time to peak drug concentration (T<sub>max</sub>) values of 4 and 3 h, respectively. After reaching maximum plasma concentration (C<sub>max</sub>), the disposition of ocedurenone appeared to be biphasic. The geometric mean t<sub>1/2</sub> values for the moderate hepatic impairment group and normal hepatic function group were 75.6 and 65.7 h, respectively. Ocedurenone systemic exposure, as assessed by area under the plasma concentration-time curve (AUC) was 23.5-26.6% lower in subjects with moderate hepatic impairment versus subjects with normal hepatic function, whereas C<sub>max</sub> was 41.2% lower. Ocedurenone was determined to be > 99.7% bound to total protein in plasma. Hepatic impairment appeared not to change plasma protein binding or the unbound free fraction. Ocedurenone was safe and well-tolerated in all participants.</p><p><strong>Conclusions: </strong>Considering the long half-life of ocedurenone and previously completed clinical studies using 0.25 mg and 0.5 mg doses demonstrating efficacy and safety, the observed decreases in AUC and C<sub>max</sub> do not warrant a dose adjustment in patients with moderate hepatic impairment. A single 0.5 mg dose of ocedurenone was safe and well-tolerated when administered to subjects with moderate hepatic impairment and subjects with normal hepatic function. CLINICAL TRIAL IDENTIFIER ( WWW.</p><p><strong>Clinicaltrials: </strong>GOV ): NCT04534699.</p>","PeriodicalId":11939,"journal":{"name":"European Journal of Drug Metabolism and Pharmacokinetics","volume":null,"pages":null},"PeriodicalIF":1.9000,"publicationDate":"2024-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10904433/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"European Journal of Drug Metabolism and Pharmacokinetics","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1007/s13318-024-00879-3","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/2/8 0:00:00","PubModel":"Epub","JCR":"Q3","JCRName":"PHARMACOLOGY & PHARMACY","Score":null,"Total":0}
引用次数: 0

Abstract

Background and objectives: Ocedurenone (KBP-5074) is a novel nonsteroidal mineralocorticoid receptor antagonist that has demonstrated safety and efficacy in clinical trials in patients with uncontrolled hypertension and stage 3b/4 chronic kidney disease. The aim of this study was to assess the pharmacokinetics, safety, and tolerability of ocedurenone in individuals with moderate hepatic impairment.

Methods: This study was an open-label, nonrandomized, multi-center study investigating the pharmacokinetics, safety, and tolerability of a single dose of 0.5 mg ocedurenone administered orally in male and female subjects with moderate hepatic impairment (Child-Pugh B, score 7-9) compared with subjects with normal hepatic function. Serial blood samples were obtained from predose through 264 h postdose for analysis of ocedurenone concentrations using a validated liquid chromatography-tandem mass spectrometry method. Free ocedurenone concentrations in plasma were determined ex vivo using equilibrium dialysis.

Results: Following a single oral dose of 0.5 mg ocedurenone administered to subjects with moderate hepatic impairment and subjects with normal hepatic function, ocedurenone was steadily absorbed with median time to peak drug concentration (Tmax) values of 4 and 3 h, respectively. After reaching maximum plasma concentration (Cmax), the disposition of ocedurenone appeared to be biphasic. The geometric mean t1/2 values for the moderate hepatic impairment group and normal hepatic function group were 75.6 and 65.7 h, respectively. Ocedurenone systemic exposure, as assessed by area under the plasma concentration-time curve (AUC) was 23.5-26.6% lower in subjects with moderate hepatic impairment versus subjects with normal hepatic function, whereas Cmax was 41.2% lower. Ocedurenone was determined to be > 99.7% bound to total protein in plasma. Hepatic impairment appeared not to change plasma protein binding or the unbound free fraction. Ocedurenone was safe and well-tolerated in all participants.

Conclusions: Considering the long half-life of ocedurenone and previously completed clinical studies using 0.25 mg and 0.5 mg doses demonstrating efficacy and safety, the observed decreases in AUC and Cmax do not warrant a dose adjustment in patients with moderate hepatic impairment. A single 0.5 mg dose of ocedurenone was safe and well-tolerated when administered to subjects with moderate hepatic impairment and subjects with normal hepatic function. CLINICAL TRIAL IDENTIFIER ( WWW.

Clinicaltrials: GOV ): NCT04534699.

Abstract Image

新型非甾体类矿物皮质激素受体拮抗剂 Ocedurenone(KBP-5074)在中度肝功能不全患者中的药代动力学。
背景和目的:Ocedurenone (KBP-5074)是一种新型非甾体类矿物皮质激素受体拮抗剂,在未控制的高血压和3b/4期慢性肾病患者的临床试验中已证明其安全性和有效性。本研究旨在评估 ocedurenone 在中度肝功能损害患者中的药代动力学、安全性和耐受性:本研究是一项开放标签、非随机、多中心研究,旨在调查中度肝功能损伤(Child-Pugh B,7-9分)男性和女性受试者与肝功能正常受试者相比,口服单剂量0.5毫克奥昔洛酮的药代动力学、安全性和耐受性。从用药前到用药后 264 小时内连续采集血液样本,采用经过验证的液相色谱-串联质谱法分析 ocedurenone 的浓度。采用平衡透析法测定血浆中的游离氧舒酮浓度:结果:中度肝功能损害和肝功能正常的受试者单次口服0.5毫克的奥塞曲酮后,奥塞曲酮被稳定吸收,达到峰值药物浓度(Tmax)的中位时间分别为4小时和3小时。在达到最大血浆浓度(Cmax)后,奥塞曲酮似乎呈双相分布。中度肝功能损害组和正常肝功能组的 t1/2 几何平均值分别为 75.6 小时和 65.7 小时。根据血浆浓度-时间曲线下面积(AUC)评估,中度肝功能损害组与肝功能正常组相比,欧塞酮的全身暴露量降低了 23.5-26.6%,而 Cmax 降低了 41.2%。经测定,Ocedurenone 与血浆中总蛋白的结合率大于 99.7%。肝功能损害似乎不会改变血浆蛋白结合率或未结合的游离部分。所有参与者都能安全耐受欧舒酮:考虑到奥塞曲酮的半衰期较长,而且之前完成的0.25毫克和0.5毫克剂量的临床研究也证明了其疗效和安全性,因此观察到的AUC和Cmax下降并不意味着需要对中度肝功能损害患者的剂量进行调整。对于中度肝功能损害和肝功能正常的受试者,单次服用0.5毫克剂量的奥昔洛酮是安全且耐受性良好的。临床试验 IDENTIFIER ( WWW.Clinicaltrials: GOV ):NCT04534699。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
求助全文
约1分钟内获得全文 求助全文
来源期刊
CiteScore
3.70
自引率
0.00%
发文量
64
审稿时长
>12 weeks
期刊介绍: Hepatology International is a peer-reviewed journal featuring articles written by clinicians, clinical researchers and basic scientists is dedicated to research and patient care issues in hepatology. This journal focuses mainly on new and emerging diagnostic and treatment options, protocols and molecular and cellular basis of disease pathogenesis, new technologies, in liver and biliary sciences. Hepatology International publishes original research articles related to clinical care and basic research; review articles; consensus guidelines for diagnosis and treatment; invited editorials, and controversies in contemporary issues. The journal does not publish case reports.
×
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