Guangzhou Bay Area Institute of Biomedicine, Guangdong Lewwin Pharmaceutical Research Institute Co., Ltd., Guangdong Provincial Key Laboratory of Drug Non-Clinical Evaluation and Research, Guangzhou, China.
Experimental Center, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China.
J Ocul Pharmacol Ther. 2023 Dec;39(10):735-743. doi: 10.1089/jop.2023.0035. Epub 2023 Aug 9.
To evaluate the pharmacokinetics of sirolimus eye drops following topical instillation in rabbits. The study included 2 experiments. In single-dose pharmacokinetic study, rabbits received a single bilateral instillation of 0.05% sirolimus eye drops (0.5 mg/mL, 50 μL/eye). In repeat-dose pharmacokinetic study, 0.05% sirolimus eye drops (0.5 mg/mL, 50 μL/eye/time) were instilled into both eyes of rabbits four times a day for 6 consecutive days and one time on day 7. Whole blood, tears, aqueous humor, cornea, and conjunctiva samples were collected. Sirolimus concentration was determined by a validated liquid chromatography-tandem mass spectrometry. Sirolimus was hardly detected in plasma or aqueous humor after either single or repeated dosing. The C of sirolimus in tears, cornea, and conjunctiva after a single instillation was 163.34 ± 69.30 μg/g, 150.56 ± 84.98 ng/g, and 113.22 ± 49.82 ng/g, respectively. As the number of instillation elevated, the C of sirolimus was increased to 486.18 ± 297.93 μg/g, 418.63 ± 41.07 ng/g, and 314.25 ± 63.74 ng/g, respectively. In repeat-dose administration, the steady state of sirolimus concentration was achieved on the third day. Ocular exposure to sirolimus after single and repeated dosing, based on AUC, was highest in tears, followed by cornea and conjunctiva. Compared with single administration, a significant increase in sirolimus exposure as measured by AUC was observed in tears, cornea, and conjunctiva following repeated administration. Topical administration of sirolimus eye drops results in extensive distribution of sirolimus in tears, cornea, and conjunctiva, while aqueous humor and systemic exposure were negligible. Repeat-dose administration increases sirolimus exposure in tears, cornea, and conjunctiva.
评估兔眼局部滴注西罗莫司滴眼液后的药代动力学。该研究包括 2 项实验。在单次剂量药代动力学研究中，兔双眼单次各滴注 0.05%西罗莫司滴眼液（0.5mg/ml，50μL/眼）。在重复剂量药代动力学研究中，兔双眼每天各滴注 0.05%西罗莫司滴眼液（0.5mg/ml，50μL/眼/次）4 次，连续 6 天，第 7 天滴注 1 次。采集全血、泪液、房水、角膜和结膜样本。采用验证后的液相色谱-串联质谱法测定西罗莫司浓度。单次或重复给药后，血浆或房水中几乎检测不到西罗莫司。单次滴注后泪液、角膜和结膜中西罗莫司 C 分别为 163.34±69.30μg/g、150.56±84.98ng/g 和 113.22±49.82ng/g。随着滴眼次数的增加，西罗莫司 C 分别增加至 486.18±297.93μg/g、418.63±41.07ng/g 和 314.25±63.74ng/g。重复给药时，第 3 天达到西罗莫司浓度的稳态。基于 AUC，单次和重复给药后西罗莫司的眼部暴露量以泪液最高，其次是角膜和结膜。与单次给药相比，重复给药后泪液、角膜和结膜中西罗莫司暴露量的 AUC 显著增加。西罗莫司滴眼液局部给药可使西罗莫司广泛分布于泪液、角膜和结膜，而房水和全身暴露量可忽略不计。重复给药可增加泪液、角膜和结膜中西罗莫司的暴露量。
