PILOT STUDY OF TUDCA DOSING AND PHARMACOKINETICS IN NONHUMAN PRIMATES

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 子项目的主要研究者可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 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，没有研究显示口服给药的靶器官获益。 在对患有视网膜疾病的人类患者进行全面研究之前，我们需要更好地了解口服给药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。 具体而言，我们建议确定在稳态血浆浓度下达到啮齿动物研究中发现的治疗视网膜水平的口服剂量，并进一步确定玻璃体和CSF水平是否可以作为TUDCA视网膜水平的替代物。 选择的动物是恒河猴，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学方面具有相似性。 该研究将为设计视网膜退行性疾病患者的临床试验提供关键信息。

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.