Pathogenesis: Emphasis on Dry Eye and the Role of the Lacrimal Functional Unit in Sjögren’s Syndrome

Stern, Michael E.; Pflugfelder, Stephen C.

doi:10.1007/978-1-60327-957-4_13

Cited by 1 publication

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“…From pioneering work by Stern et al describing the pathogenesis of immune-mediated 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 Understanding PK at the site of action, demonstrating free drug exposure in these tissues, and determining if the drug achieves desired target concentrations are important factors in drug development. 12 For CsA to inhibit calcineurin in target tissues, an estimated tissue concentration of 10–20 μg/g has to be achieved.…”

Section: Discussionmentioning

confidence: 99%

Ocular Distribution of Cyclosporine Following Topical Administration of OTX-101 in New Zealand White Rabbits

Weiss

Kramer²

2019

Journal of Ocular Pharmacology and Therapeutics

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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 Ò ; 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.

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Section: Discussionmentioning

confidence: 99%