Pharmacokinetics of Azithromycin, Levofloxacin, and Ofloxacin in Rabbit Extraocular Tissues After Ophthalmic Administration

Abstract

IntroductionAzithromycin demonstrates high tissue distribution and prolonged elimination half-life. In this study, we monitored the pharmacokinetics of a single ophthalmic administration of 1% azithromycin ophthalmic solution containing polycarbophil in the extraocular tissues, including the eyelid, and compared it with that of two commercial ophthalmic products, 1.5% levofloxacin ophthalmic solution and 0.3% ofloxacin ophthalmic ointment.MethodsRabbits were treated with either a single topical administration of 1% azithromycin ophthalmic solution, 1.5% levofloxacin ophthalmic solution, or 0.3% ofloxacin ophthalmic ointment. The eyelid, conjunctiva, and cornea were collected at 0.25, 0.5, 1, 2, 4, 8, and 24 h post-administration. Tissue samples were pretreated for drug concentration measurements by ultra-performance liquid chromatography-tandem mass spectrometry. Pharmacokinetic parameters were determined by non-compartmental analysis.ResultsAzithromycin was rapidly absorbed, and its levels remained near the observed maximum concentrations for up to 24 h post-administration in all tissue. In contrast, extraocular tissue concentrations of levofloxacin and ofloxacin decreased with time. The maximum concentrations of azithromycin, levofloxacin, and ofloxacin were 35.6, 34.1, and 55.1 µg/g in the eyelid, 44.2, 46.8, and 20.4 µg/g in the conjunctiva, and 79.9, 18.0, and 2.21 µg/g in the cornea, respectively. The values of the area under the curve from 0 to 24 h after administration of azithromycin, levofloxacin, and ofloxacin were 602, 58.5, and 267 µg·h/g in the eyelid, 837, 43.2, and 51.9 µg·h/g in the conjunctiva, and 1250, 26.4, and 5.46 µg h/g in the cornea, respectively.ConclusionThe drug concentrations of azithromycin and levofloxacin were relatively comparable among the extraocular tissues following topical administration of the respective ophthalmic solutions, whereas the concentrations of ofloxacin varied following dosing of its ophthalmic ointment. The slow elimination profile in any extraocular tissue of rabbits was unique to azithromycin, and led to the demonstration of high exposures of azithromycin in all extraocular tissues after ophthalmic administration.FundingThis research and Rapid Service Fees were supported by Senju Pharmaceutical Co., Ltd.

A Bioequivalence Study With Pharmacokinetic Endpoints for Azithromycin Eye Drops

“…For 1% azithromycin ophthalmic solution containing polycarbophil, availability was confirmed in the ocular tissues of rabbits, including tears, conjunctiva, and cornea. With a single drop of 1% azithromycin, the concentrations were sustained near the observed maximum levels for up to 24 hours post‐administration in all ocular tissue 14–16 . Similarly, following the instillation of a single drop of azithromycin eye drops in healthy volunteers, the mean tear concentration of azithromycin remained above the minimum inhibitory concentration for 24 hours 5,6 .…”

“…With a single drop of 1% azithromycin, the concentrations were sustained near the observed maximum levels for up to 24 hours post-administration in all ocular tissue. [14][15][16] Similarly, following the instillation of a single drop of azithromycin eye drops in healthy volunteers, the mean AUC 0-∞ , area under the curve from time zero to infinity; AUC 0-t , area under the curve from time zero to the specified time; CI, confidence intervall C max , peak concentration. Data are expressed as mean ± SD.…”

Improved Outcome of Pythium Keratitis With a Combined Triple Drug Regimen of Linezolid and Azithromycin

“…Although we did not find direct evidence for the superiority of azithromycin eye drops over ointment, the results of animal studies comparing an eye drop formulation with eye ointment reported that the eye drop formulation is likely to be more effective for the treatment of a keratitis than an ointment because corneal penetration of the eye drops was better. 14,15 Oral linezolid was chosen based on the result of the in vitro susceptibility of the Pythium culture isolates where it fared well for the largest zone of inhibition, low minimum inhibitory concentration value, 7 and high concentrations achieved in aqueous and vitreous. 16 The analysis of clinical features of the infiltrate revealed midstromal tentacles (47.61%) and dot-shaped infiltrates (71.42%) as a frequent feature.…”