A Toxicological Evaluation of a Single Dose, 90 Day Sustained Release Travoprost Punctum Plug in Canines

Abstract

Purpose: Pre-clinically evaluate the ocular and systemic toxicity of the Travoprost Punctum Plug (OTX-TP3) following insertion over a 90 day period in dogs.

Methods: OTX-TP3 is a biodegradable hydrogel matrix containing encapsulated travoprost. Upon insertion into the canaliculus, the hydrogel swells to conform to the space enabling plug retention & travoprost release over 90 days. The hydrogel is conjugated with fluorescein to aid visualization. Baseline ophthalmic exams & clinical pathology were conducted. OTX-TP3 was inserted into the vertical canaliculus bilaterally in 16 beagles; a control group (n=16) received a placebo punctum plug & contralaterally a sham insertion procedure. Dosing was ensured (95+%) by replacing lost plugs &/or extending the dosing period. Ophthalmic examinations were performed periodically (slit lamp biomicroscopy, fluorescein staining, fundoscopy, and tonometry). Plasma & tear fluid were collected. Canines were sacrificed at approximately Day 91 of dosing or Day 121 (30 day recovery period) & complete necropsies conducted. Histology was assessed on ocular tissues and nasal turbinates. The study followed FDA 21 CFR, Part 58 GLP for Non Clinical Laboratory Studies.

Results: Punctum plugs were well tolerated overall during the study. A high incidence of punctum plug retention was observed. Systemically, there were no test article-related effects. Posterior segment ophthalmic examinations were similar for all eyes. Consistent with travoprost ocular drops, anterior segment exam findings were limited to mild redness & congestion in the conjunctiva of test article eyes; this was not noted at recovery & not considered adverse. There were no test article related macroscopic observations. All microscopic findings, such as cell infiltration & dilation of the canaliculi, were related to expansion of canalicular tissue from the plugs & resolved during the recovery period. Lack of detectable travoprost in plasma indicated no systemic exposure, while travoprost in tear fluid demonstrated local delivery throughout the dosing period.

Conclusions: The presence OTX-TP3 in the puncta were well tolerated. Results showed no systemic toxicity. A single OTX-TP3 dose demonstrated local drug delivery throughout the course of the study. Clinically, a biodegradable, single dose of sustained release travoprost may offer higher therapy compliance and more convenient alternative to eye drops.