University of Florida, Gainesville, Florida, USA.
Brookseyes LLC, Alachua Florida, Florida, USA.
J Ocul Pharmacol Ther. 2022 Jul-Aug;38(6):424-432. doi: 10.1089/jop.2022.0030. Epub 2022 Jul 14.
To determine the pharmacokinetics of a proprietary liposomal sirolimus (LS) formulation in ocular tissues and plasma following a single subconjunctival (SCJ) injection in Dutch belted rabbits (DBR). Analytical methods for detection of LS in plasma, aqueous humor (AH), vitreous humor (VH), retina, combined retina/choroid/retinal pigment epithelium, sclera, and iris/ciliary body were developed to examine samples. Thirty male DBR were subconjunctivally injected in both eyes with 0.1 mL of LS of 1,000 μg/mL. At selected times post-injection, ocular tissues and whole blood samples were obtained. Sirolimus concentrations were measured using liquid chromatography/tandem mass spectrometry. No LS was detected in serum or AH at any time. All other examined ocular tissues had quantifiable amounts of LS at all times. LS levels were highest in sclera and lowest in VH, suggesting LS followed the supraciliary and suprachoroidal spaces to reach the posterior segment. Vitreous peak of sirolimus levels occurred at 2 h, and the sclera adjacent to the injection peaked at both 2 and 96 h. LS levels in remaining ocular tissues peaked at 6 h and decreased with time, persisting at presumed therapeutic levels on day 22. LS can quickly diffuse into posterior intraocular tissues after SCJ injection without reaching quantifiable levels in AH or serum in DBR. Peak levels occurred in posterior intraocular tissues at 6 h and persisted in all tissues after 3 weeks. SCJ LS in DBR is safe, has a stable pharmacokinetic profile, and should be considered for further study in human trials for autoimmune ophthalmopathies.
为了确定单次结膜下（SCJ）注射后一种新型脂质体西罗莫司（LS）制剂在荷兰兔眼部组织和血浆中的药代动力学。开发了用于检测血浆、房水（AH）、玻璃体（VH）、视网膜、视网膜/脉络膜/视网膜色素上皮联合、巩膜和虹膜/睫状体中 LS 的分析方法，以检查样本。30 只雄性荷兰兔双眼结膜下注射 1,000μg/mL 的 0.1mL LS。在注射后选定的时间点，采集眼部组织和全血样本。使用液相色谱/串联质谱法测量西罗莫司浓度。在任何时间都未在血清或 AH 中检测到 LS。所有其他检查的眼部组织在任何时间都有可量化的 LS 量。LS 水平在巩膜中最高，在 VH 中最低，表明 LS 遵循巩膜上和脉络膜上的空间到达后节。玻璃体中西罗莫司水平的峰值出现在 2 小时，注射部位附近的巩膜在 2 小时和 96 小时均达到峰值。其余眼部组织的 LS 水平在 6 小时达到峰值，并随时间减少，在第 22 天仍保持在假定的治疗水平。LS 可在结膜下注射后迅速扩散到眼后组织，而在荷兰兔的 AH 或血清中未达到可量化的水平。6 小时后在眼后组织中达到峰值，并在 3 周后在所有组织中持续存在。结膜下 LS 在荷兰兔中是安全的，具有稳定的药代动力学特征，应考虑在自身免疫性眼病的人类试验中进一步研究。
