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Ezra R. Lowe, Sherwin Jiang, Joel W. Proksch; Rapid Ocular Penetration of Ganciclovir with Topical Administration of Zirgan® to Rabbits. Invest. Ophthalmol. Vis. Sci. 2011;52(14):3258.
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Zirgan (ganciclovir ophthalmic gel, 0.15%, Bausch + Lomb) is an antiviral ophthalmic gel approved by the FDA in 2009. This study was conducted in 2010 to characterize the rapid ocular penetration of ganciclovir following topical administration of the marketed product to rabbits with healthy eyes and following removal of the corneal epithelium.
Dutch Belted rabbits (96 total) were assigned to one of three dose groups: Group 1: single dose, intact eyes; Group 2: single dose, de-epithelialized eyes; Group 3: repeated dosing, de-epithelialized eyes. The corneal epithelium was removed from animals in Group 2 and 3 using ethanol and gentle scraping with a Gill knife. Animals received a single 40-µL dose of Zirgan or 5 doses/day (every 2 h) for up to 5 days. Tissue samples (tear, aqueous humor, conjunctiva, cornea, iris/ciliary body, vitreous, choroid, retina, and plasma) were collected at 5, 15, 30 min and 1, 2, 4, 8, and 24 h after a single dose and after the 5th dose on Day 1. Samples were also collected 30 min after the 5th dose on Days 2-5. Ganciclovir concentrations were determined using a selective LC/MS/MS method.
Following topical administration of Zirgan to rabbits with intact eyes, ganciclovir was rapidly absorbed with measurable concentrations observed 5 min after dosing. Removal of the corneal epithelium resulted in an increased rate and extent of penetration. In aqueous humor, a ganciclovir Cmax of 0.5 µg/mL was observed at 1 h for intact animals compared to a ganciclovir Cmax of 26.6 µg/mL at 15 min for de-epithelialized animals. Exposure to ganciclovir in aqueous humor after a single dose, based on AUC, increased approximately 24-fold after removal of the corneal epithelium. Systemic exposure to ganciclovir was low and similar for the intact and de-epithelialized animals.
The present study design afforded a robust characterization of the rate of penetration of ganciclovir and the findings increase our understanding of the disposition of ganciclovir in ocular tissues during the initial minutes after topical dosing. Topical administration of Zirgan results in rapid penetration of ganciclovir within 5 minutes and affords therapeutic levels in ocular tissues, consistent with the demonstrated clinical efficacy of Zirgan in the treatment of acute herpetic keratitis.
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