A Phase I, Randomized, Open-label, Single Dose, 2 Period, Crossover Study to Evaluate the Effect of Food on the Pharmacokinetics of Linerixibat Tablets in Healthy Adult Participants

This study will evaluate the effect of food on the Pharmacokinetic (PK) and Pharmacodynamic (PD) parameters of linerixibat administered in fed and fasted states in heathy adult participants

开始日期2022-08-11

申办/合作机构

GSK Plc

NCT05393076

/ Completed临床1期

A Phase 1, Open-label, Single-dose Study to Evaluate the Pharmacokinetics and Safety of Linerixibat in Adults With Moderate Hepatic Impairment and Healthy Matched Control Participants

This is a phase 1, open-label, single-dose study in adults with moderate hepatic impairment (defined as Child-Pugh B cirrhosis) and matched healthy control participants with normal hepatic function. All participants in both cohorts (moderate hepatic impairment and matched healthy controls) will receive a single dose of the study drug, linerixibat. The purpose of this study is to assess the effect of hepatic impairment on the pharmacokinetics (PK) and safety of linerixibat.

开始日期2022-07-19

申办/合作机构

GSK Plc

NCT05133830

/ Completed临床1期

A Two-part, Phase 1, Open-label, Randomized, Parallel-arm, Fixed Sequence, Drug-drug Interaction Study to Investigate the Effect of Linerixibat on Plasma Concentrations of Obeticholic Acid and Conjugates in Healthy Adult Participants

This study aims to investigate the effect of linerixibat on plasma concentrations of obeticholic acid (OCA) and its conjugates in healthy adult participants to inform the potential for drug interaction with coadministration of linerixibat and OCA.

开始日期2021-11-23

申办/合作机构

GSK Plc

100 项与利奈昔巴特相关的临床结果

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100 项与利奈昔巴特相关的转化医学

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100 项与利奈昔巴特相关的专利（医药）

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项与利奈昔巴特相关的文献（医药）

2025-03-01·CPT-Pharmacometrics & Systems Pharmacology

Analysis of C4 Concentrations to Predict Impact of Patient‐Reported Diarrhea Associated With the Ileal Bile Acid Transporter Inhibitor Linerixibat

Article

作者: Carreño, Fernando ; Swift, Brandon ; Collins, Jon ; de Souza, Andrea Ribeiro ; Mehta, Rashmi

ABSTRACT:

Linerixibat, an ileal bile acid transporter (IBAT) inhibitor, is being evaluated for the treatment of pruritus in primary biliary cholangitis (PBC). Diarrhea is commonly reported with this drug class as IBAT inhibition redirects bile acids (BA) to the colon. Serum 7‐alpha‐hydroxy‐4‐cholesten‐3‐one (C4) measurement is a validated method to identify BA diarrhea. To inform dose selection, we characterized the relationship between linerixibat dose, C4 levels, and patient‐reported bother on the gastrointestinal symptom rating scale (GSRS) diarrhea question. A kinetic‐pharmacodynamic model was developed using data from five Phase 1/2 trials, to describe the effect of linerixibat dose (1–180 mg) and regimen (once/twice daily) on C4 concentrations over time. GSRS data from patients with PBC and pruritus in the Phase 2b GLIMMER study (NCT02966834) were used to develop a proportional odds model to predict the probability of a score of 1–7 (no–very severe discomfort) to the question “Have you been bothered by diarrhea during the past week?” in relation to linerixibat dose. The two models were linked to describe the linerixibat dose‐C4‐diarrhea bother relationship. Models were validated using graphical and numerical assessment and visual predictive checks. Linerixibat caused dose‐dependent increases in C4 until saturation (~180 mg total daily dose). Increased C4 concentrations trended with increased GSRS diarrhea scores. Simulations demonstrated increases in moderate‐to‐very severe (≥ 4) diarrhea scores with increasing linerixibat dose. Increases in patient‐reported diarrhea scores were linerixibat dose‐dependent. Selecting an optimal dose that maximizes linerixibat's ability to improve pruritus while minimizing patient‐reported diarrhea bother is important to support treatment adherence.

2024-10-01·BIOMEDICINE & PHARMACOTHERAPY

Studies on absorption mechanism and pharmacokinetic properties of albendazole-bile acid conjugate: In vivo and in vitro

Article

作者: Tang, Shizhen ; Liu, Jingshuai ; Guo, Zhimei ; Nie, Kaili ; Hu, Chunhui

PURPOSE:

To improve the oral bioavailability of albendazole (ABZ), a series of albendazole-bile acid conjugates (ABCs) were synthesized. ABC's transmembrane transport mechanism and in vivo pharmacokinetic properties were preliminarily studied.

METHODS:

The transmembrane transport mechanism of ABCs was studied using the Caco-2 monolayer cell model and intestinal perfusion model. The concentration of ABCs and ABZ were evaluated using High-Performance Liquid Chromatography (HPLC) and HPLC-Mass Spectrometry (HPLC-MS/MS).

RESULTS:

Compared to ABZ, better permeability was observed for different types and concentrations of ABCs using the Caco-2 monolayer cell model, with ABC-C8 showing the highest permeability. The transmembrane transport of ABCs was affected by ASBT inhibitors, indicating an ASBT-mediated active transport mechanism. Additionally, introducing cholic acid resulted in ABZ no longer being a substrate for P-gp, MRP2, and BCRP, effectively reversing ABZ efflux. In vivo unidirectional intestinal perfusion results in rats showed that ABCs altered the absorption site of ABZ from the jejunum to the ileum. The absorption efficiency of ABCs in each intestinal segment was higher than that of ABZ, and the transmembrane transport efficiency decreased with increasing concentrations of ASBT inhibitors. This further confirmed the presence of both passive diffusion and ASBT-mediated active transport mechanisms in the transport of ABCs. The solubility of ABCs in gastric juice and pharmacokinetics in rats showed that ABZ-C4 exhibited enhanced solubility. Moreover, ABCs significantly increased oral bioavailability compared to ABZ, with ABC-C4 showing an approximately 31-fold increase in bioavailability.

CONCLUSION:

The transmembrane transport mechanism of ABCs involves a combination of ASBT-mediated active transport and passive diffusion. Moreover, the incorporation of BAs successfully reverses the efflux of ABZ by efflux proteins. Among the synthesized conjugates, ABC-C4 demonstrated superior dissolution behavior both in vitro and in vivo.

2024-09-01·Liver International

Serum bile acid change correlates with improvement in pruritus in patients with primary biliary cholangitis receiving linerixibat

Article

作者: McLaughlin, Megan M. ; Carreño, Fernando ; Casillas, Linda ; Swift, Brandon ; Karatza, Eleni ; Fettiplace, James ; Kremer, Andreas E. ; Mukherjee, Sumanta ; Lennie, Janelle

Abstract:

Background & Aims:

Total serum bile acid (TSBA) levels are elevated in patients with primary biliary cholangitis (PBC) and may mediate cholestatic pruritus. Linerixibat, an ileal bile acid transporter inhibitor, improved pruritus in patients with PBC. We explored the relationship between linerixibat dose, TSBA concentration, and pruritus.

Methods:

Data from Phase 1/2 trials were used to develop a population kinetic‐pharmacodynamic model to characterize the linerixibat dose–TSBA relationship. Individual Bayesian parameter estimates for participants in the GLIMMER study were used to derive the area under the TSBA concentration curve over 24 h (AUC0–24). Time‐matched post hoc estimates of AUC0–24 were correlated with pruritus reported on a 0–10 numerical rating scale. Baseline TSBA concentration was correlated with change from baseline (ΔBL) in monthly itch score (MIS). ΔBL in model‐estimated TSBA AUC0–24 was correlated with time‐matched ΔBL in weekly itch score (WIS) or MIS.

Results:

Linerixibat dose dependently reduced TSBA AUC0–24, reaching steady state after 5 days. Baseline TSBA levels in GLIMMER did not correlate with ΔBL in MIS. ΔBL in TSBA AUC0–24 correlated with improved WIS over 12 weeks of treatment (r = 0.52, p < 0.0001). Of participants with a ≥30% decrease in TSBA AUC0–24, 60% were pruritus responders (≥2‐point improvement in WIS from baseline).

Conclusions:

Linerixibat treatment leads to rapid, dose‐dependent TSBA reductions. Baseline TSBA levels do not correlate with on‐treatment pruritus change, suggesting they do not predict linerixibat response. Change in TSBA AUC0–24 correlates significantly with, and can be predictive of, pruritus improvement in patients with PBC.

项与利奈昔巴特相关的新闻（医药）

2025-07-10

·同写意

三药同日获批！亚盛医药白血病疗法领衔

同写意年度巨献！！7月25-26日，邀您相聚金鸡湖畔，与5000人一起为中国医药创新“同写意”！7月10日，NMPA最新批件信息显示，三款新药在中国获批上市。它们分别来自亚盛医药、旺山旺水和诺贝仁医药，针对适应症包括慢性淋巴细胞白血病/小淋巴细胞淋巴瘤、勃起功能障碍以及儿童期伴随神经发育障碍的入睡困难改善。其中，亚盛医药的APG-2575作为全球第二个上市的Bcl-2抑制剂，此次获批尤其引人关注。该药物于2024年11月向NMPA提交上市申请，仅用8个月时间就完成审评流程，此次获批有望为中国数十万慢性淋巴细胞白血病患者提供全新的无化疗治疗选择。TONACEA01三药齐发亚盛医药此次获批的利沙托克拉（lisaftoclax，APG-2575片）适应症为：用于既往经过至少包含BTK抑制剂在内的一种系统治疗的成人慢性淋巴细胞白血病/小淋巴细胞淋巴瘤（CLL/SLL）患者，也成为中国首个上市用于治疗CLL/SLL的Bcl-2抑制剂。此次NDA是基于一项在中国开展的关键注册II期临床研究（APG2575CC201）结果。该研究旨在评估APG-2575单药治疗R/R CLL/SLL患者的有效性和安全性，主要终点指标为总缓解率（ORR）。对于BTK抑制剂和/或免疫化疗治疗失败的病人，利沙托克拉展现出优异疗效，ORR达到预设的研究终点。同时，利沙托克拉安全性表现突出，研究中未发生肿瘤溶解综合征（TLS）副作用，血液学毒性发生率低且程度可控，非血液学毒性发生率低且多为1-2级。亚盛医药已构建起丰富的血液肿瘤产品矩阵。除APG-2575外，该公司首个上市产品三代BCR-ABL抑制剂耐立克已进入国家医保目录。据东吴证券预测，APG-2575在中国和美国市场销售额有望在2034年分别达到20亿元和35亿元，展现出巨大的市场潜力。除APG-2575外，此次获批的另外两款药物同样填补了特定领域的治疗空白。诺贝仁医药的儿童睡眠障碍药物褪黑素颗粒是针对神经发育障碍儿童入睡困难的精准解决方案。临床数据显示，该药物能显著缩短患儿入睡时间，改善睡眠连续性，且不良反应发生率低。根据诺贝仁医药官网，这是该公司研发的褪黑激素受体激动剂（商品名为Melatobel），其作为改善儿童期伴随神经性发育障碍的入睡困难的药品，已于2020年3月在日本获得上市许可。旺山旺水的勃起功能障碍新药盐酸司美那非片则为男性健康领域带来创新治疗方案，本次获批用于治疗勃起功能障碍（ED）。该药物是一种新型高选择性的5型磷酸二酯酶（PDE5）抑制剂，通过新颖的作用机制改善海绵体血流量，为磷酸二酯酶抑制剂治疗效果不佳的患者提供替代选择。TONACEA02进入收获期2025年成为中国创新药的爆发之年。就在6月以来，多款重磅新药密集获批。金赛药业宣布其痛风创新药伏欣奇拜单抗获批上市，可使痛风患者半年内复发风险降低87%。礼来的GLP-1R/GIPR双重激动剂替尔泊肽注射液在中国获批，成为全球首个用于治疗成人肥胖患者阻塞性睡眠呼吸暂停的药物。信达生物全球首个GCG/GLP-1双靶减重药物玛仕度肽在复旦大学附属中山医院开出上海首张处方，为中国超重肥胖人群提供新选择。新药审评审批体系持续优化。徐诺药业的甲苯磺酸艾贝司他片与葛兰素史克的利奈昔巴特片近日拟纳入优先审评，再次体现了中国对于具有明显临床价值的创新药品的加速支持政策。荣昌生物的ADC药物维迪西妥单抗新适应症上市申请也于7月8日获受理，拟用于联合治疗HER2表达的局部晚期或转移性尿路上皮癌患者。声明：本文由同写意内容团队整理，转载请注明出处。

申请上市上市批准

2025-07-04

·医药观澜

GSK口服靶向新药「利奈昔巴特片」在中国拟纳入优先审评

今日（7月4日），中国国家药监局药品审评中心（CDE）官网公示，葛兰素史克（GSK）申报的利奈昔巴特片拟纳入优先审评，适用于治疗原发性胆汁性胆管炎（PBC）成人患者的胆汁淤积性瘙痒。公开资料显示，这是GSK在研的回肠胆汁酸转运蛋白（IBAT）抑制剂linerixibat。该产品的新药申请（NDA）已经于今年6月获美国FDA及欧洲药品管理局（EMA）受理，适应症为治疗原发性胆汁性胆管炎（PBC）成人患者的胆汁淤积性瘙痒。PBC作为一种胆汁淤积性肝病，会导致肝脏胆汁流动受阻。由此引发的循环胆汁酸过量被认为是胆汁淤积性瘙痒症（一种无法通过抓挠缓解的内源性瘙痒）的致病因素。该瘙痒可发生于PBC疾病或生化控制的任何阶段，严重程度各异，约90%的PBC患者会出现此症状。虽然PBC一线治疗可控制约70%患者的病情，但无法减轻瘙痒的严重程度或影响。胆汁淤积性瘙痒症是一种可能致残的严重病症，患者会出现睡眠障碍、疲劳、生活质量下降，甚至可能在未出现肝功能衰竭的情况下需进行肝移植。Linerixibat是一种IBAT口服抑制剂，具有治疗与PBC相关的胆汁淤积性瘙痒的潜力。通过抑制胆汁酸重吸收，linerixibat可减少循环中多种瘙痒介质。美国FDA和EMA已授予linerixibat用于治疗与PBC相关的胆汁淤积性瘙痒的孤儿药资格。Linerixibat此前已经在3期临床试验GLISTEN取得积极结果。GLISTEN是一项双盲、随机、安慰剂对照的3期试验，共纳入238名伴胆汁淤积性瘙痒的PBC患者，初始按1:1比例随机分配至活性药物组和安慰剂组。主要分析评估了linerixibat相较安慰剂的疗效和安全性。GLISTEN试验达到主要终点，结果显示，接受linerixibat治疗的患者（n=119）在24周内瘙痒显著改善，优于安慰剂组（n=119）。通过最严重瘙痒程度的数值评分量表（WI-NRS）进行评估，两组之间的最小二乘均值差为-0.72（95% CI：-1.15，-0.28，p=0.001）。该结果显示，linerixibat有望缓解PBC患者的一项主要症状——顽固性瘙痒。该研究还达成多个关键次要终点，包括第2周瘙痒评分改善及24周内瘙痒相关睡眠干扰评分的改善，具体表现如下：瘙痒改善起效迅速，第2周即优于安慰剂组，差异具有统计学意义（最小二乘均值差为-0.71，95% CI：-1.07，-0.34，p<0.001），且疗效在整个试验周期内持续维持。在24周的治疗周期中，与安慰剂相比，linerixibat显著改善了瘙痒引起的睡眠干扰，该症状对患者生活质量影响显著。到第24周，linerixibat组中有56%的患者瘙痒评分改善具有临床意义（WI-NRS降低≥3分），而安慰剂组为43%，治疗组之间的差异为13%（95% CI：0，27）。参考资料：[1]中国国家药监局药品审评中心（CDE）官网. Retrieved Jun 28, From https://www.cde.org.cn/main/xxgk/listpage/4b5255eb0a84820cef4ca3e8b6bbe20c[2]Linerixibat accepted for review by the European Medicines Agency for cholestatic pruritus in patients with primary biliary cholangitis (PBC). From https://www.gsk.com/en-gb/media/press-releases/linerixibat-accepted-for-review-by-the-european-medicines-agency/[3] GLISTEN phase III trial results show linerixibat significantly improves cholestatic pruritus (relentless itch) in primary biliary cholangitis (PBC). Retrieved May 8, 2025, from https://www.gsk.com/en-gb/media/press-releases/glisten-phase-iii-trial-results-show-linerixibat-significantly-improves-cholestatic-pruritus/免责声明：本文仅作信息交流之目的，文中观点不代表药明康德立场，亦不代表药明康德支持或反对文中观点。本文也不是治疗方案推荐。如需获得治疗方案指导，请前往正规医院就诊。

优先审批孤儿药临床3期临床结果

2025-06-06

·PipelineReview

Linerixibat New Drug Application (NDA) accepted for review by the US FDA for cholestatic pruritus in patients with primary biliary cholangitis (PBC)

LONDON, UK I June 02, 2025 I GSK plc (LSE/NYSE: GSK) today announced the US Food and Drug Administration (FDA) has accepted for review the NDA for linerixibat, an investigational targeted inhibitor of the ileal bile acid transporter (IBAT), for the treatment of cholestatic pruritus in patients with PBC, a rare autoimmune liver disease. The Prescription Drug User Fee Act (PDUFA) goal date is 24 March 2026. Kaivan Khavandi, SVP, Global Head, Respiratory, Immunology & Inflammation R&D, GSK, said: “The FDA’s acceptance of this file is an important milestone in the development of linerixibat. We believe that linerixibat has the potential to make a difference in the lives of patients living with relentless itch associated with PBC and its related sleep interference. These are debilitating symptoms which currently have very limited treatment options.” The application is based on positive data from the GLISTEN phase III trial, presented in May at the European Association for the Study of the Liver (EASL) Congress. GLISTEN met both primary and key secondary endpoints demonstrating a rapid, significant and sustained improvement in cholestatic pruritus and itch-related sleep interference versus placebo. The safety profile of linerixibat was consistent with previous studies and the mechanism of IBAT inhibition. Linerixibat is currently not approved anywhere in the world. About cholestatic pruritus in PBC In PBC, a cholestatic liver disease, bile flow from the liver is disrupted. The resulting excess bile acids in circulation are thought to play a causal role in cholestatic pruritus, an internal itch that cannot be relieved by scratching. Pruritus can occur at any stage of PBC disease or biochemical control, and is experienced in varying degrees of severity by up to 90% of people living with PBC. 1 The first line treatment for PBC controls disease in approximately 70% of patients, but does not reduce the severity or impact of the pruritus. 2,3 Cholestatic pruritus is a serious condition that can be debilitating, with patients experiencing sleep disturbance, fatigue, impaired quality of life and even sometimes requiring liver transplantation in the absence of liver failure. 3,4 About linerixibat (GSK2330672) Linerixibat is an IBAT inhibitor, a targeted oral agent with potential to treat cholestatic pruritus (itch) associated with the rare autoimmune liver disease known as PBC. By inhibiting bile acid re-uptake, linerixibat reduces multiple mediators of pruritus in circulation. The US Food and Drug Administration and the European Medicines Agency have granted orphan drug designation for linerixibat in the treatment of cholestatic pruritus in patients with PBC. About the GLISTEN trial GLISTEN is a double-blind, randomised, placebo-controlled, phase III trial (NCT04950127; GSK study 212620) conducted in 238 PBC patients with cholestatic pruritus initially enrolled equally into active and placebo arms (n=119 each). The primary analysis evaluated the efficacy and safety of linerixibat compared with placebo. Participants with moderate to severe itch were enrolled. Participants initially received either linerixibat or placebo and had the potential to cross over in a part B of the trial. Primary and secondary outcome measures were assessed using a 0-10 numerical rating scale for worst itch and itch-related sleep interference. Stable use of guideline suggested anti-itch therapy was permitted. The trial was the first truly global PBC study completed in 19 countries including the Americas, Europe, China and Japan. About GSK research in hepatology GSK is currently investigating multiple potential treatments for patients with liver disease. In addition to PBC, we are also investigating potential treatments for chronic hepatitis B, alcohol-related liver disease (ALD), and metabolic dysfunction-associated steatohepatitis (MASH). About GSK GSK is a global biopharma company with a purpose to unite science, technology, and talent to get ahead of disease together. Find out more at gsk.com. References SOURCE: GlaxoSmithKline

临床3期临床结果申请上市孤儿药

100 项与利奈昔巴特相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
D11539	-	-	DB11729

研发状态

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适应症	最高研发状态	国家/地区	公司	日期
胆汁淤积性瘙痒	申请上市	美国	GSK Plc	2025-06-02
原发性胆汁性胆管炎	申请上市	美国	GSK Plc	2025-06-02
瘙痒	临床2期	澳大利亚	GSK Plc	2017-01-11
2型糖尿病	临床2期	美国	GSK Plc	2013-08-01

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临床结果

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT04950127 (GLISTEN, Company_Website 1 \| Company_Website 2) 人工标引	临床3期	原发性胆汁性胆管炎	238	Linerixibat	壓餘廠鬱齋壓鏇願遞製(醖觸製遞築遞繭簾餘鑰): Difference (LS Mean) = -0.72 (95% CI, -1.15 ~ -0.28), P-Value = 0.001 达到更多	积极	2024-11-19
				Placebo
NCT03992014 (CTgov)	临床1期	胆汁淤积	6	[14C] Linerixibat+Linerixibat (Linerixibat 90 mg Oral Tablets + [14C] Linerixibat 100 μg IV)	構壓夢獵糧網構網餘淵(膚遞獵願齋構艱簾範鏇) = 鏇壓網鑰繭遞願鹽壓窪鏇餘範構膚構鹹網夢鏇 (夢簾餘繭淵範膚壓夢觸, 25.8) 更多	-	2020-06-26
				[14C]-Linerixibat ([14C]-Linerixibat 90 Milligram Oral Solution)	糧糧醖簾夢積艱餘襯積(繭築鑰鹽糧繭築顧積構) = 選簾齋夢憲觸鬱觸壓鑰窪觸遞鏇鬱醖觸壓網構 (繭廠夢觸網襯簾蓋鹽蓋, 95.3) 更多
NCT02202161 (CTgov)	临床2期	2型糖尿病	70	placebo+metformin+GSK2330672 (Placebo)	選繭觸壓窪膚鏇獵膚繭(窪鹹齋鏇築築顧願鏇鹽) = 鏇選膚膚鏇鬱膚積廠齋鬱淵壓廠鏇鏇襯鬱艱衊 (餘鹽廠鬱鏇遞製願顧獵, 16.357) 更多	-	2017-11-06
				GSK2330672 (GSK2330672 10 mg BID)	選繭觸壓窪膚鏇獵膚繭(窪鹹齋鏇築築顧願鏇鹽) = 顧膚夢蓋構憲鹹鬱淵鑰鬱淵壓廠鏇鏇襯鬱艱衊 (餘鹽廠鬱鏇遞製願顧獵, 6.500) 更多
NCT01929863 (CTgov)	临床2期	2型糖尿病	16	Metformin+GSK2330672 (Treatment A-GSK2330672 + Metformin)	選簾築築衊蓋遞遞鬱膚 = 憲製製窪願獵壓築鏇夢願憲艱膚鹽襯願鬱壓醖 (餘鑰選鑰簾築齋繭鹽齋, 壓鹽觸製鹹顧願憲簾製 ~ 窪繭選製窪淵憲遞積觸) 更多	-	2017-08-16
				Placebo+Metformin (Treatment B-Placebo + Metformin)	選簾築築衊蓋遞遞鬱膚 = 壓艱繭齋夢鏇齋鏇鏇衊願憲艱膚鹽襯願鬱壓醖 (餘鑰選鑰簾築齋繭鹽齋, 鬱憲衊鏇衊獵觸齋餘齋 ~ 窪艱淵衊簾製衊鹽顧憲) 更多
NCT01899703 (Pubmed \| Lancet) 人工标引	临床2期	瘙痒 \| 原发性胆汁性胆管炎	22	GSK2330672	鏇壓蓋壓壓鬱鬱鹹餘鏇(製願鏇遞衊廠願膚顧範) = Diarrhoea was the most frequent adverse event during treatment with GSK2330672 (seven with GSK2330672 vs one with placebo) and headache was the most frequent adverse event during treatment with placebo (seven with placebo vs six with GSK2330672). 膚鑰餘獵鬱顧鏇膚齋積 (壓鹹蓋鹽積襯遞廠膚窪 )	积极	2017-03-18
				Placebo