PILOT STUDY OF TUDCA DOSING AND PHARMACOKINETICS IN NONHUMAN PRIMATES

TUDCA 在非人类灵长类动物中的剂量和药代动力学试点研究

• 批准号: 8357872
• 负责人: MARTHA NEURINGER
• 金额: $ 4.36万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-01 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8357872
• 关键词: Animal Model; Animals; Bile Acids; Clinical Trials Design; Degenerative Disorder; Dose; Drug Kinetics; Funding; Goals; Grant; Human; Macaca mulatta; Metabolism; National Center for Research Resources; Neurodegenerative Disorders; Neuroprotective Agents; Oral; Organ; Patients; Pharmacodynamics; Physiology; Pilot Projects; Plasma; Primates; Principal Investigator; Regimen; Research; Research Infrastructure; Resources; Retinal; Retinal Degeneration; Retinal Diseases; Rodent; Rodent Model; Source; Therapeutic; United States National Institutes of Health; cost; nonhuman primate; tauroursodeoxycholic acid

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Tauroursodeoxycholic acid (TUDCA) is a bile acid that has shown promise as a neuroprotective agent in rodent models of retinal degeneration and neurodegenerative disease. However, there are no studies showing target organ benefit with oral dosing. Before full-scale studies are undertaken in human patients with retinal disease, we need to better understand the pharmacokinetics and pharmacodynamics of the orally dosed compound in a relevant animal model. This study has the goal of identifying a potentially therapeutic dose and dosing regimen of TUDCA. Specifically, we propose to determine an oral dose that, at steady state plasma concentration, achieves a retinal level found to be therapeutic in rodent studies, and further, to determine whether vitreous and CSF levels can function as surrogates for retinal levels of TUDCA. The animal of choice is the rhesus macaque because of the similarity in bile acid metabolism and retinal physiology in humans and nonhuman primates. The study will provide key information needed for the design of clinical trials in human patients with retinal degenerative diseases.

该子项目是利用资源的众多研究子项目之一 由 NIH/NCRR 资助的中心拨款提供。子项目的主要支持 并且子项目的主要研究者可能是由其他来源提供的， 包括其他 NIH 来源。 子项目可能列出的总成本 代表子项目使用的中心基础设施的估计数量， NCRR 赠款不直接向子项目或子项目工作人员提供资金。 牛磺熊去氧胆酸 (TUDCA) 是一种胆汁酸，在视网膜变性和神经退行性疾病的啮齿动物模型中显示出作为神经保护剂的前景。 然而，没有研究表明口服给药对靶器官有益。 在对人类视网膜疾病患者进行全面研究之前，我们需要更好地了解口服化合物在相关动物模型中的药代动力学和药效学。 本研究的目的是确定 TUDCA 的潜在治疗剂量和给药方案。 具体来说，我们建议确定口服剂量，在稳态血浆浓度下，达到在啮齿动物研究中发现具有治疗作用的视网膜水平，并进一步确定玻璃体和脑脊液水平是否可以作为 TUDCA 视网膜水平的替代。 选择的动物是恒河猴，因为人类和非人类灵长类动物的胆汁酸代谢和视网膜生理学相似。 该研究将为人类视网膜退行性疾病患者的临床试验设计提供所需的关键信息。