健康志愿者口服 TQS-168 的首次随机安慰剂对照人体研究:评估安全性、耐受性、药代动力学、药效学和食物效应。

IF 3.1 3区 医学 Q2 MEDICINE, RESEARCH & EXPERIMENTAL
Jonas Hannestad, Steven Smith, Andrew Lam, Janet Hurt, Nicole Harada, Richard Kim, Abhirup Das, Juliana Brunello, Gareth Whitaker, David Chalmers, Faria Senjoti, Wu Lin, James Coghill, Yogesh Bansal, Sharan Sidhu, Vanessa Zann, Enchi Liu
{"title":"健康志愿者口服 TQS-168 的首次随机安慰剂对照人体研究:评估安全性、耐受性、药代动力学、药效学和食物效应。","authors":"Jonas Hannestad,&nbsp;Steven Smith,&nbsp;Andrew Lam,&nbsp;Janet Hurt,&nbsp;Nicole Harada,&nbsp;Richard Kim,&nbsp;Abhirup Das,&nbsp;Juliana Brunello,&nbsp;Gareth Whitaker,&nbsp;David Chalmers,&nbsp;Faria Senjoti,&nbsp;Wu Lin,&nbsp;James Coghill,&nbsp;Yogesh Bansal,&nbsp;Sharan Sidhu,&nbsp;Vanessa Zann,&nbsp;Enchi Liu","doi":"10.1111/cts.70064","DOIUrl":null,"url":null,"abstract":"<p>TQS-168, a first-in-class small-molecule inducer of peroxisome proliferator-activated receptor gamma coactivator 1-alpha gene expression, is in development for the treatment of amyotrophic lateral sclerosis. A single-ascending-dose (SAD) and multiple-ascending-dose (MAD) study of TQS-168 was carried out in healthy male subjects to investigate safety, tolerability, pharmacokinetics (PK), food effect, and preliminary pharmacodynamic effects (PD). Since solubility enhancement could be beneficial, assessment of three formulations was incorporated into the study using an integrated rapid manufacturing and clinical testing approach. Dosing in the SAD part was initiated with a crystalline methylcellulose (MC) suspension, and then spray-dried dispersion (SDD) and hot-melt extrusion (HME) suspensions were evaluated. The HME and SDD formulations showed two and fourfold higher exposure than the MC suspension, respectively, and the SDD formulation was selected for progression to subsequent SAD and MAD cohorts, in which there was further investigation of the food effect on exposure in addition to assessments of safety, tolerability, PK, and PD. <i>C</i><sub>max</sub> and AUC plasma exposures of TQS-168 were supra-proportional at higher doses, irrespective of formulation. Median <i>T</i><sub>max</sub> for TQS-168 occurred between 0.5 and 4.0 h post-dose and occurred later with higher doses. Geometric mean half-lives (<i>T</i><sub>1/2</sub>) for TQS-168 were independent of formulation and food, ranging from 3.2 to 10.5 h following single doses and 4.1 to 7.3 h following multiple doses. Food blunted TQS-168 <i>C</i><sub>max</sub> but had minimal impact on AUC. TQS-168 was considered to be safe and generally well tolerated following single and multiple oral doses. The SDD formulation was selected for future patient studies.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"17 11","pages":""},"PeriodicalIF":3.1000,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11559592/pdf/","citationCount":"0","resultStr":"{\"title\":\"A randomized, placebo-controlled first-in-human study of oral TQS-168 in healthy volunteers: Assessment of safety, tolerability, pharmacokinetics, pharmacodynamics, and food effect\",\"authors\":\"Jonas Hannestad,&nbsp;Steven Smith,&nbsp;Andrew Lam,&nbsp;Janet Hurt,&nbsp;Nicole Harada,&nbsp;Richard Kim,&nbsp;Abhirup Das,&nbsp;Juliana Brunello,&nbsp;Gareth Whitaker,&nbsp;David Chalmers,&nbsp;Faria Senjoti,&nbsp;Wu Lin,&nbsp;James Coghill,&nbsp;Yogesh Bansal,&nbsp;Sharan Sidhu,&nbsp;Vanessa Zann,&nbsp;Enchi Liu\",\"doi\":\"10.1111/cts.70064\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p>TQS-168, a first-in-class small-molecule inducer of peroxisome proliferator-activated receptor gamma coactivator 1-alpha gene expression, is in development for the treatment of amyotrophic lateral sclerosis. A single-ascending-dose (SAD) and multiple-ascending-dose (MAD) study of TQS-168 was carried out in healthy male subjects to investigate safety, tolerability, pharmacokinetics (PK), food effect, and preliminary pharmacodynamic effects (PD). Since solubility enhancement could be beneficial, assessment of three formulations was incorporated into the study using an integrated rapid manufacturing and clinical testing approach. Dosing in the SAD part was initiated with a crystalline methylcellulose (MC) suspension, and then spray-dried dispersion (SDD) and hot-melt extrusion (HME) suspensions were evaluated. The HME and SDD formulations showed two and fourfold higher exposure than the MC suspension, respectively, and the SDD formulation was selected for progression to subsequent SAD and MAD cohorts, in which there was further investigation of the food effect on exposure in addition to assessments of safety, tolerability, PK, and PD. <i>C</i><sub>max</sub> and AUC plasma exposures of TQS-168 were supra-proportional at higher doses, irrespective of formulation. Median <i>T</i><sub>max</sub> for TQS-168 occurred between 0.5 and 4.0 h post-dose and occurred later with higher doses. Geometric mean half-lives (<i>T</i><sub>1/2</sub>) for TQS-168 were independent of formulation and food, ranging from 3.2 to 10.5 h following single doses and 4.1 to 7.3 h following multiple doses. Food blunted TQS-168 <i>C</i><sub>max</sub> but had minimal impact on AUC. TQS-168 was considered to be safe and generally well tolerated following single and multiple oral doses. The SDD formulation was selected for future patient studies.</p>\",\"PeriodicalId\":50610,\"journal\":{\"name\":\"Cts-Clinical and Translational Science\",\"volume\":\"17 11\",\"pages\":\"\"},\"PeriodicalIF\":3.1000,\"publicationDate\":\"2024-11-13\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11559592/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Cts-Clinical and Translational Science\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://onlinelibrary.wiley.com/doi/10.1111/cts.70064\",\"RegionNum\":3,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"MEDICINE, RESEARCH & EXPERIMENTAL\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cts-Clinical and Translational Science","FirstCategoryId":"3","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1111/cts.70064","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"MEDICINE, RESEARCH & EXPERIMENTAL","Score":null,"Total":0}
引用次数: 0

摘要

TQS-168是一种可诱导过氧化物酶体增殖体激活受体γ辅助激活剂1-α基因表达的首创小分子药物,目前正在开发用于治疗肌萎缩性脊髓侧索硬化症。在健康男性受试者中开展了 TQS-168 的单剂量(SAD)和多剂量(MAD)研究,以考察其安全性、耐受性、药代动力学(PK)、食物效应和初步药效学效应(PD)。由于提高溶解度可能是有益的,因此在研究中采用了快速生产和临床测试综合方法,对三种制剂进行了评估。在 SAD 部分,首先使用结晶甲基纤维素(MC)悬浮剂进行给药,然后对喷雾干燥分散剂(SDD)和热熔挤出悬浮剂(HME)进行评估。HME和SDD制剂的暴露量分别比MC悬浮剂高出2倍和4倍,因此SDD制剂被选入后续的SAD和MAD组别,在这些组别中,除了安全性、耐受性、PK和PD评估外,还进一步研究了食物对暴露量的影响。无论配方如何,TQS-168在较高剂量时的Cmax和AUC血浆暴露量均超比例。TQS-168的中位Tmax出现在服药后0.5到4.0小时之间,剂量越大,Tmax出现越晚。TQS-168 的几何平均半衰期(T1/2)与制剂和食物无关,单次给药后为 3.2 至 10.5 小时,多次给药后为 4.1 至 7.3 小时。食物会减弱 TQS-168 的 Cmax,但对 AUC 的影响很小。单次和多次口服 TQS-168 均被认为安全且耐受性良好。未来的患者研究将选择 SDD 制剂。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

A randomized, placebo-controlled first-in-human study of oral TQS-168 in healthy volunteers: Assessment of safety, tolerability, pharmacokinetics, pharmacodynamics, and food effect

A randomized, placebo-controlled first-in-human study of oral TQS-168 in healthy volunteers: Assessment of safety, tolerability, pharmacokinetics, pharmacodynamics, and food effect

TQS-168, a first-in-class small-molecule inducer of peroxisome proliferator-activated receptor gamma coactivator 1-alpha gene expression, is in development for the treatment of amyotrophic lateral sclerosis. A single-ascending-dose (SAD) and multiple-ascending-dose (MAD) study of TQS-168 was carried out in healthy male subjects to investigate safety, tolerability, pharmacokinetics (PK), food effect, and preliminary pharmacodynamic effects (PD). Since solubility enhancement could be beneficial, assessment of three formulations was incorporated into the study using an integrated rapid manufacturing and clinical testing approach. Dosing in the SAD part was initiated with a crystalline methylcellulose (MC) suspension, and then spray-dried dispersion (SDD) and hot-melt extrusion (HME) suspensions were evaluated. The HME and SDD formulations showed two and fourfold higher exposure than the MC suspension, respectively, and the SDD formulation was selected for progression to subsequent SAD and MAD cohorts, in which there was further investigation of the food effect on exposure in addition to assessments of safety, tolerability, PK, and PD. Cmax and AUC plasma exposures of TQS-168 were supra-proportional at higher doses, irrespective of formulation. Median Tmax for TQS-168 occurred between 0.5 and 4.0 h post-dose and occurred later with higher doses. Geometric mean half-lives (T1/2) for TQS-168 were independent of formulation and food, ranging from 3.2 to 10.5 h following single doses and 4.1 to 7.3 h following multiple doses. Food blunted TQS-168 Cmax but had minimal impact on AUC. TQS-168 was considered to be safe and generally well tolerated following single and multiple oral doses. The SDD formulation was selected for future patient studies.

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
Cts-Clinical and Translational Science
Cts-Clinical and Translational Science 医学-医学:研究与实验
CiteScore
6.70
自引率
2.60%
发文量
234
审稿时长
6-12 weeks
期刊介绍: Clinical and Translational Science (CTS), an official journal of the American Society for Clinical Pharmacology and Therapeutics, highlights original translational medicine research that helps bridge laboratory discoveries with the diagnosis and treatment of human disease. Translational medicine is a multi-faceted discipline with a focus on translational therapeutics. In a broad sense, translational medicine bridges across the discovery, development, regulation, and utilization spectrum. Research may appear as Full Articles, Brief Reports, Commentaries, Phase Forwards (clinical trials), Reviews, or Tutorials. CTS also includes invited didactic content that covers the connections between clinical pharmacology and translational medicine. Best-in-class methodologies and best practices are also welcomed as Tutorials. These additional features provide context for research articles and facilitate understanding for a wide array of individuals interested in clinical and translational science. CTS welcomes high quality, scientifically sound, original manuscripts focused on clinical pharmacology and translational science, including animal, in vitro, in silico, and clinical studies supporting the breadth of drug discovery, development, regulation and clinical use of both traditional drugs and innovative modalities.
×
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