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Sidney L Weiss, William Kramer, Poonam Velagaleti, Brian C Gilger; Ocular Distribution of Cyclosporine Following Topical Administration of OTX-101 in New Zealand White Rabbits. Invest. Ophthalmol. Vis. Sci. 2018;59(9):2677. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
OTX-101 is a novel, clear aqueous nanomicellar solution of cyclosporine (CsA) under development for the treatment of dry eye disease. We present the results of a pharmacokinetic study conducted in New Zealand White (NZW) rabbits to determine the ocular tissue distribution of OTX-101 compared with a currently marketed formulation of CsA.
Rabbits in the Single Dose Phase received a single bilateral instillation of OTX-101 0.05% CsA or Restasis® (cyclosporine ophthalmic emulsion) 0.05%, as a comparator. In the Repeat Dosing Phase, OTX-101 (0.01%, 0.05%, or 0.1% CsA) or the comparator was instilled bilaterally 4 times per day for 7 days. CsA levels were analyzed in samples of 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 tissue and whole blood concentrations were analyzed using liquid chromatography-tandem mass spectrometry (LC-MS/MS).
Samples from a total of 112 rabbits were analyzed. Following both single and repeat administration of study drugs, CsA was distributed extensively in ocular tissues, but minimal systemic exposure was detected (mean Cmax < 7 ng/mL in whole blood at the highest OTX-101 dose [0.1% 4 times per day]). Following a single dose, higher concentrations of CsA were observed in all ocular tissues/fluids following administration of OTX-101 0.05% CsA over the comparator except for the superior eyelid, tears and vitreous humor, where it was lower. The highest concentrations of CsA in ocular tissues following a single OTX-101 instillation occurred in the third eyelid (Cmax = 1199.8 ng/g), superior bulbar conjunctiva (Cmax = 861.5 ng/g), and cornea (Cmax = 806.5ng/g). Ocular tissue concentrations of CsA increased in a dose-related manner following repeated administration of the OTX-101 formulations; Cmax for the cornea was 1,542.5 ng/g, 5,410.0 ng/g, and 8,122.5 ng/g, for the 0.01%, 0.05%, or 0.1% CsA concentrations, respectively. No systemic accumulation of CsA was observed following repeat dosing.
OTX-101 0.05%, a clear aqueous nanomicellar formulation of CsA, produces higher tissue levels of CsA in the conjunctiva and cornea than the comparator after single and repeat dosing. OTX-101 0.1% produced proportionally higher tissue concentrations than OTX-101 0.05% and was well tolerated.
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.
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