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Ocular Distribution of Cyclosporine Following Topical Administration of OTX-101 in New Zealand White Rabbits
Purpose: Evaluate the ocular distribution, tolerability, and systemic exposure of cyclosporine (CsA) in New Zealand white rabbits following topical administration of OTX-101, a novel, clear aqueous nanomicellar solution developed for the treatment of dry eye disease (DED). Methods: The study design...
Autores principales: | , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Mary Ann Liebert, Inc., publishers
2019
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6735319/ https://www.ncbi.nlm.nih.gov/pubmed/31355703 http://dx.doi.org/10.1089/jop.2018.0106 |
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author | Weiss, Sidney L. Kramer, William G. |
author_facet | Weiss, Sidney L. Kramer, William G. |
author_sort | Weiss, Sidney L. |
collection | PubMed |
description | Purpose: Evaluate the ocular distribution, tolerability, and systemic exposure of cyclosporine (CsA) in New Zealand white rabbits following topical administration of OTX-101, a novel, clear aqueous nanomicellar solution developed for the treatment of dry eye disease (DED). Methods: The study design included single- and repeat-dose phases. In the single-dose phase, rabbits received a single instillation of OTX-101 0.05% or CsA ophthalmic emulsion 0.05% (Restasis(®); Allergan, Irvine, CA) as a comparator. In the repeat-dosing phase, OTX-101 (0.01%, 0.05%, or 0.1% CsA) or comparator was instilled 4 times per day for 7 days. Samples collected included whole blood, tears, and ocular tissues/fluids (aqueous humor, choroid-retina, conjunctiva, cornea, superior eyelid, third eyelid, iris/ciliary body, lacrimal gland, lens, sclera, and vitreous humor). CsA concentrations were analyzed using liquid chromatography-tandem mass spectrometry. Results: Analysis included samples from 112 rabbits. The highest concentration of CsA following a single OTX-101 0.05% instillation occurred in the third eyelid (C(max) = 1,200 ng/g). Concentrations of CsA in the cornea and superior bulbar conjunctiva increased in a dose-related manner following repeated administration of OTX-101 formulations; C(max) [T(max) (h)] for cornea was 1,543 ng/g (6.50), 5,410 ng/g (7.0), and 8,123 ng/g (6.50), for 0.01%, 0.05%, and 0.1% CsA concentrations, respectively; for superior bulbar conjunctiva was 726 ng/g (6.50), 1,468 ng/g (6.50), and 2,080 ng/g (6.25), respectively. Conclusions: OTX-101 topical ophthalmic instillation resulted in extensive distribution of CsA in ocular tissues, particularly in target tissues for DED (cornea and conjunctiva), while systemic exposure was negligible. |
format | Online Article Text |
id | pubmed-6735319 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Mary Ann Liebert, Inc., publishers |
record_format | MEDLINE/PubMed |
spelling | pubmed-67353192019-09-10 Ocular Distribution of Cyclosporine Following Topical Administration of OTX-101 in New Zealand White Rabbits Weiss, Sidney L. Kramer, William G. J Ocul Pharmacol Ther Original Articles Purpose: Evaluate the ocular distribution, tolerability, and systemic exposure of cyclosporine (CsA) in New Zealand white rabbits following topical administration of OTX-101, a novel, clear aqueous nanomicellar solution developed for the treatment of dry eye disease (DED). Methods: The study design included single- and repeat-dose phases. In the single-dose phase, rabbits received a single instillation of OTX-101 0.05% or CsA ophthalmic emulsion 0.05% (Restasis(®); Allergan, Irvine, CA) as a comparator. In the repeat-dosing phase, OTX-101 (0.01%, 0.05%, or 0.1% CsA) or comparator was instilled 4 times per day for 7 days. Samples collected included whole blood, tears, and ocular tissues/fluids (aqueous humor, choroid-retina, conjunctiva, cornea, superior eyelid, third eyelid, iris/ciliary body, lacrimal gland, lens, sclera, and vitreous humor). CsA concentrations were analyzed using liquid chromatography-tandem mass spectrometry. Results: Analysis included samples from 112 rabbits. The highest concentration of CsA following a single OTX-101 0.05% instillation occurred in the third eyelid (C(max) = 1,200 ng/g). Concentrations of CsA in the cornea and superior bulbar conjunctiva increased in a dose-related manner following repeated administration of OTX-101 formulations; C(max) [T(max) (h)] for cornea was 1,543 ng/g (6.50), 5,410 ng/g (7.0), and 8,123 ng/g (6.50), for 0.01%, 0.05%, and 0.1% CsA concentrations, respectively; for superior bulbar conjunctiva was 726 ng/g (6.50), 1,468 ng/g (6.50), and 2,080 ng/g (6.25), respectively. Conclusions: OTX-101 topical ophthalmic instillation resulted in extensive distribution of CsA in ocular tissues, particularly in target tissues for DED (cornea and conjunctiva), while systemic exposure was negligible. Mary Ann Liebert, Inc., publishers 2019-09-01 2019-09-05 /pmc/articles/PMC6735319/ /pubmed/31355703 http://dx.doi.org/10.1089/jop.2018.0106 Text en © Sidney L. Weiss and William G. Kramer 2019; Published by Mary Ann Liebert, Inc. This Open Access article is distributed under the terms of the Creative Commons License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Original Articles Weiss, Sidney L. Kramer, William G. Ocular Distribution of Cyclosporine Following Topical Administration of OTX-101 in New Zealand White Rabbits |
title | Ocular Distribution of Cyclosporine Following Topical Administration of OTX-101 in New Zealand White Rabbits |
title_full | Ocular Distribution of Cyclosporine Following Topical Administration of OTX-101 in New Zealand White Rabbits |
title_fullStr | Ocular Distribution of Cyclosporine Following Topical Administration of OTX-101 in New Zealand White Rabbits |
title_full_unstemmed | Ocular Distribution of Cyclosporine Following Topical Administration of OTX-101 in New Zealand White Rabbits |
title_short | Ocular Distribution of Cyclosporine Following Topical Administration of OTX-101 in New Zealand White Rabbits |
title_sort | ocular distribution of cyclosporine following topical administration of otx-101 in new zealand white rabbits |
topic | Original Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6735319/ https://www.ncbi.nlm.nih.gov/pubmed/31355703 http://dx.doi.org/10.1089/jop.2018.0106 |
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