PILOT STUDY OF TUDCA DOSING AND PHARMACOKINETICS IN NONHUMAN PRIMATES

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 牛磺酸脱氧胆酸(TUDCA)是一种胆汁酸，在视网膜退行性变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，没有研究表明口服剂量对靶器官有好处。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复方在相关动物模型中的药代动力学和药效学。这项研究的目的是确定TUDCA的潜在治疗剂量和给药方案。具体地说，我们建议确定一个口服剂量，在稳态血浆浓度下，达到在啮齿动物研究中被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视网膜水平的替代品。选择猕猴是因为人类和非人类灵长类动物在胆汁酸代谢和视网膜生理方面的相似之处。这项研究将为设计人类视网膜退行性疾病患者的临床试验提供所需的关键信息。

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.