Abstract
Purpose :
OTX-CSI is a resorbable intracanalicular insert designed to deliver cyclosporine in a sustained-release fashion on to the ocular surface, developed for the treatment of patients with dry eye disease. Here we evaluate the ocular and systemic toxicity and pharmacokinetics of OTX-CSI in beagles over 90 days.
Methods :
54 beagles were assigned into three groups: OTX-CSI (elevated dose: 0.7 mg) inserted bilaterally into the canaliculus of 24 beagles (OD: Formulation A (shorter persisting vehicle); OS: Formulation B (longer persisting vehicle); placebo vehicle (identical to OTX-CSI insert, but without drug) inserted in 24 beagles in a similar manner, and a sham group (n=6 beagles). Ocular toxicity was evaluated by ophthalmic exams and histopathological findings of ocular tissues. Systemic toxicity was evaluated based on clinical observations and clinical pathology. Tear fluid and plasma samples were collected at 1, 2, 4 hrs. and 1, 7, 30, 60 and 90 days and drug level concentrations were determined by liquid chromatography with tandem mass spectrometry (LC/MS/MS).
Results :
The toxicity study summary of findings is presented in Table 1. Microscopic observations of relevant ocular tissues and surrounding adnexa was normal (score of 0). Clinical observations were normal and systemic histopathology findings were comparable between active and control groups. Mean cyclosporine concentrations in tear fluid (Table 2) ranged from 2.2 to 4.1 µg/mL. Cyclosporine concentrations in all plasma samples were below the lower limit of quantitation (2.0 ng/mL).
Conclusions :
OTX-CSI intracanalicular insert was well tolerated in the beagle eyes. No evidence of systemic toxicity found. OTX-CSI demonstrates sustained release and continual dose exposure over 90 days. Cyclosporine levels in tear fluid delivered daily by OTX-CSI are above the target therapeutic level for 90 days (≥ 0.24 µg/mL cyclosporine concentrations required for t-cell immunomodulation). A maximum feasible dose of approximately 0.7 mg cyclosporine per insert in the OTX-CSI in this study in beagle dogs did not establish a maximum tolerated dose, thereby supporting the safe use of a lower cyclosporine dose (~0.36 mg) in future human clinical studies.
This is a 2020 ARVO Annual Meeting abstract.