Pharmacokinetics of Sirolimus Eye Drops Following Topical Ocular Administration in Rabbits.

Purpose: To evaluate the pharmacokinetics of sirolimus eye drops following topical instillation in rabbits.

Methods

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.

Results

Sirolimus was hardly detected in plasma or aqueous humor after either single or repeated dosing. The Cmax 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 Cmax 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 AUC0-t, was highest in tears, followed by cornea and conjunctiva. Compared with single administration, a significant increase in sirolimus exposure as measured by AUC0-t was observed in tears, cornea, and conjunctiva following repeated administration.

Conclusions

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.