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Ocular Bioavailability and Systemic Levels of an Ophthalmic Formulation of Azithromycin, ISV-401

¹ Pre-Clinical Research, InSite Vision Inc, Alameda, CA, United States
² Formulation, InSite Vision Inc, Alameda, CA, United States

Commercial Relationships: E.C. Si, InSite Vision, Inc. E; L.M. Bowman, InSite Vision, Inc. E; S.D. Roy, InSite Vision, Inc. E.

Abstract

Purpose: Azithromycin is a broad spectrum antibiotic widely used to treat various systemic infections. We have incorporated the drug in DuraSite, a proprietary polymeric drug delivery system, with a code name ISV-401. We investigated the levels of azithromycin in the tears, conjunctiva, and plasma in rabbits after a single ocular application of 0.5% and 1% ISV-401.
Methods: A drop of 0.5% or 1% ISV-401 was instilled into both eyes of a New Zealand White rabbit. At 0.5, 1, 2, 4, 8, 12, and 24 hours post-instillation, groups of six rabbits per treatment were sacrificed. Conjunctiva were harvested from both eyes. Tear samples were collected with Schirmer strips. Plasma samples were collected by cardiac puncture. All samples were stored at -80^oC until assayed with LC/MS.
Results: Pharmacokinetic measures of 0.5% and 1% ISV-401 were shown in the following table. There appeared to be a linear relationship between formulation concentration and conjunctival C_max and AUC. Tear concentrations leveled off at 4 hours post instillation resulting in a zero elimination constant for both formulations. Conjunctival concentrations decreased at a much slower rate. 7.1 ± 1.8 µg/g and 16.1 ± 1.6 µg/g azithromycin remained in the conjunctiva 24 hours following administration of 0.5% and 1% ISV-401 respectively. These concentrations are much higher than the MIC90 of most conjunctival pathogens. The high conjunctival concentrations are consistant with the high tissue affinity of azithromycin as reported in the literature. The peak plasma levels for 0.5% and 1% ISV-401 were 2.2 ± 0.2 ng/g and 4.4 ± 0.8 ng/g respectively . Conclusion: The ophthalmic formulations of azithromycin, ISV-401, have been shown to have long half-lives in the conjunctiva while providing very low systemic exposure. It can potentially be administered at a much lower dosing frequency than the marketed anitbiotics for the treatment of bacterial conjunctivitis.

Tissue Formulation Cmax (µg/g) Tmax (h) Kel (h-1) Terminal t1/2 (h) AUC [(µg/g) x h] Tears 0.5% ISV-401 87.1 1 0 - 413.0 1.0% ISV-401 288.4 0.5 0 - 632.8 Conjunctiva 0.5% ISV-401 30.1 0.5 0.049 14.1 394.1 1.0% ISV-401 82.6 0.5 0.051 13.5 830.5

Keywords: antibiotics/antifungals/antiparasitics • conjunctivitis • bacterial disease

© 2003, The Association for Research in Vision and Ophthalmology, Inc., all rights reserved. For permission to reproduce any part of this abstract, contact the ARVO Office at arvo{at}arvo.org.