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

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 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.

Assembling Surfactants-Mucoadhesive Polymer Nanomicelles (ASMP-Nano) for Ocular Delivery of Cyclosporine-A

“…The interest in nanomicelles has recently increased with the recent FDA approval of Cequa ® , a cyclosporine based liquid nanomicellar formulation indicated for the treatment of dry eye syndrome. The topical instillation of cyclosporine nanomicelles resulted in an expansive distribution into cornea and conjunctiva the target tissues for the treatment of dry eye syndrome [56]. In addition, the biopharmaceutical potential of nanomicelles has been enhanced by preparing active targeting nanomicelles capable of promoting active transport of drugs in the posterior segments of the eye [57].…”

<p>A Review of Topical Cyclosporine A Formulations—A Disease-Modifying Agent for Keratoconjunctivitis Sicca</p>

“…19 A preclinical study compared the ocular distribution and tolerability of OTX-101 and CsA 0.05% emulsion in New Zealand white rabbits. 28 Following a single dosing, there was a higher CsA concentration with OTX-101 0.05% compared with CsA 0.05% emulsion in most ocular tissue samples, including the cornea (2.18-fold) and superior bulbar conjunctiva (1.76-fold) with minimal systemic exposure. 28 There was a dose-related increase in CsA with repeat dosing of OTX-101 0.05% and this also resulted in higher concentrations of CsA in ocular tissues and aqueous humor than CsA 0.05% emulsion.…”

“…28 Following a single dosing, there was a higher CsA concentration with OTX-101 0.05% compared with CsA 0.05% emulsion in most ocular tissue samples, including the cornea (2.18-fold) and superior bulbar conjunctiva (1.76-fold) with minimal systemic exposure. 28 There was a dose-related increase in CsA with repeat dosing of OTX-101 0.05% and this also resulted in higher concentrations of CsA in ocular tissues and aqueous humor than CsA 0.05% emulsion. 28 Phase 2b/3 and 3 clinical studies showed that twicedaily administration of OTX-101 0.09% was superior to vehicle in increasing tear production and improving ocular signs from baseline, including conjunctival and corneal staining in patients with KCS.…”

“…28 There was a dose-related increase in CsA with repeat dosing of OTX-101 0.05% and this also resulted in higher concentrations of CsA in ocular tissues and aqueous humor than CsA 0.05% emulsion. 28 Phase 2b/3 and 3 clinical studies showed that twicedaily administration of OTX-101 0.09% was superior to vehicle in increasing tear production and improving ocular signs from baseline, including conjunctival and corneal staining in patients with KCS. 29,30 Importantly, improvement in these objective signs was seen at and after 4 weeks of therapy.…”

Aqueous deficiency is a contributor to evaporation-related dry eye disease

“…Apart from the risk of difficulties associated with topical administration however, more frequent topical instillation to achieve better access to the lacrimal gland [40] raises the possibility of over-correcting an ocular surface imbalance of pro-inflammatory over antiinflammatory cytokines. The problems associated with accessing the lacrimal gland with topical therapy [40] are illustrated by a study involving New Zealand white rabbits and treatment with an aqueous nanomicellar Cyclosporine solution (OTX 101 0.05%) [41]. That study found that after instillation of a single topical drop, the maximum lacrimal gland concentration of Cyclosporine was only 2.7, 2.5 and 1.8% of the corneal, superior bulbar conjunctival and third eyelid concentrations, respectively [41].…”