Abstract
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 (Cmax = 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; Cmax [Tmax (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.
Highlights
Cyclosporine (CsA) is a fungal-derived peptide immunomodulatory agent with immunosuppressant activities
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)
From pioneering work by Stern et al describing the pathogenesis of immunemediated DED, it is known that for the treatment of DED, the target tissue sites of action for CsA are the conjunctiva and cornea.[10,11]
Summary
Cyclosporine (CsA) is a fungal-derived peptide immunomodulatory agent with immunosuppressant activities. Cyclosporine inhibits calcineurin, preventing the activation of T lymphocytes. Anti-inflammatory effects of CsA are associated with inhibition of cell-mediated release of proinflammatory cytokines.[1,2] Systemic administration of CsA has been used for organ recipients and in the treatment of autoimmune disorders, due to the immunosuppressant properties of the molecule.[3]. Topical ophthalmic administration of CsA is utilized in the United States for the treatment of dry eye disease (DED), a common ocular condition associated with alterations in the tear film and ocular surface inflammation.[4–6]. Topical ophthalmic administration of CsA is utilized in the United States for the treatment of dry eye disease (DED), a common ocular condition associated with alterations in the tear film and ocular surface inflammation.[4–6] Cyclosporine ophthalmic emulsion 0.05%
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