Pharmacokinetics of OTX-CSI, a Sustained Release Cyclosporine Intracanalicular Insert in Beagles

Abstract

Purpose : T-cell mediated inflammation at the ocular surface and in the lacrimal gland is a cause of dry eye disease (DED). Based on available literature, CsA concentrations above 0.24 µg/mL are sufficient for T-cell immunomodulation. Bioavailability from eye drops approximates 5% due to rapid clearance and applying this metric to commercially available twice daily 0.05% CsA emulsion eye drops, a daily dose of 1.25 µg is calculated. This study was designed to measure the cyclosporine A (CsA) concentration in beagle tear fluid (TF) following administration of a sustained release CsA intracanalicular insert, OTX-CSI, and to determine the delivered CsA dose over 28 days.

Methods : OTX-CSI, 0.4 mg CsA, was inserted bilaterally into the inferior canaliculus of 20 beagles. TF was collected at 1, 7, 14, 24 and 28 days. CsA concentrations in TF were analyzed by LC/MS/MS. A subset of OTX-CSI was explanted at 28 days, imaged and analyzed for CsA by HPLC/UV, and results were compared to the initial CsA dose to determine CsA released over 28 days.

Results : CsA concentrations in beagle TF delivered from OTX-CSI ranged from 1.1 to 2.9 µg/mL over 28 days exceeding the concentration required for immunomodulation. OTX-CSI explanted at 28 days demonstrated a daily CsA release rate of 7.0 µg/day exceeding the topical eye drops bioavailable dose.

Conclusions : OTX-CSI intracanalicular inserts have the potential to deliver an efficacious dose to the ocular surface for up to 28 days. Additional work is being done to extend this duration of activity to 3-4 months for the treatment of patients with DED.

This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.

 

CsA concentrations in beagle TF delivered from OTX-CSI over 28 days

 

The delivered dose of CsA over 28 days compared to the OTX-CSI CsA administered dose