Comprehensive Evaluation of Ocular Toxicity of Topical Levofloxacin in Rabbit and Primate Models

Abstract

Levofloxacin, the L‐isomer of ofloxacin and a potent quinolone with a broad spectrum of antibacterial activity, was evaluated in a series of toxicology studies including acute and chronic dosing in rabbits and primates with intact and injured eyes. No evidence of ocular toxicity was observed in rabbits with intact eyes that were topically instilled with levofloxacin ophthalmic solutions under various treatment regimens, including multiple dosing (four to six times daily) for up to 26 weeks at levofloxacin concentrations from 0.3% to 3%. When rabbits were repetitively instilled (10 times at 30 minute intervals) with 0.3%, 1%, or 3% levofloxacin ophthalmic solutions over a single day, they exhibited no increase in ocular irritation scores, whereas dosing with 10% and 25% levofloxacin produced dose‐dependent increases in ocular discharge, conjunctival injection and edema, corneal edema/fluorescein staining, iridic congestion, and behavioral abnormalities. Healing of 7.5 mm diameter epithelial wounds in rabbit eyes was not delayed by dosing four times daily (QID) with 0.5% or 1.5% levofloxacin in four different vehicles, with complete healing after 48 hours. The QID dosing with 3% or 6% levofloxacin retarded healing at 24 hours, but healing was complete in eyes treated with 3% levofloxacin by 72 hours after injury, and nearly complete in eyes treated with 6% levofloxacin by 96 hours. Using a similar model in primates, QID treatment with 1.5% levofloxacin produced no delay in healing of epithelial wounds or increased corneal thickness compared to glycerin vehicle, while QID treatment with 3% levofloxacin delayed healing at 24 and 48 hours after injury and increased corneal thickness for 11 days. Histological evaluation of the eyes confirmed that there was no detrimental effect to the corneal endothelium as a result of treatment with 1.5% levofloxacin. In conclusion, the results of these studies support the ocular safety of concentrations of levofloxacin up to 1.5% when administered topically to the intact or wounded eye.