Safety of the Dexamethasone Punctum Plug is Demonstrated in a Canine Toxicity Study

Abstract

 

Purpose

 

To evaluate the potential ocular toxicity, irritation and systemic toxicity of the Dexamethasone Punctum Plug (OTX-DP) after insertion in beagles over a 35-day period and the reversibility, persistence, and delayed occurrence of any toxic effects after a recovery period.

 

Methods

 

The study conformed to FDA 21 CFR, Part 58 GLP for Non Clinical Laboratory Studies. OTX-DP was inserted in the vertical canaliculus bilaterally in 16 canines. A control group of 16 canines had a blank vehicle punctum plug administered in one eye and the contralateral eye received an insertion sham procedure. Ophthalmic examinations included slit lamp biomicroscopy, fluorescein staining, fundoscopy and tonometry. Daily clinical observations, daily food checks, and weekly weight measurements were performed. Canines were sacrificed at Day 36 or after a 14 day recovery period (Day 50) and necropsy was performed. Clinical pathology samples were collected (hematology, clinical chemistry, coagulation, and urinalysis). Histopathology of the lacrimal anatomy and eye for each implant site, nasal turbinates and adrenal gland was performed. Analysis of drug in plasma and tear fluid samples was performed. Intraocular pressure (IOP) was measured over the study duration.

 

Results

 

Pharmacokinetics demonstrated dexamethasone release into canine tear fluid over the study duration (ARVO 2013 Abstract #1089). Plasma drug levels were absent demonstrating only localized delivery with no systemic exposure. The principal findings are summarized in Table One. There were no findings of ocular, local or systemic toxicity. No effects were observed on body weights, food consumption, hematology, clinical chemistry, coagulation or urinalysis. Ophthalmic examinations indicated none to only mild irritation that were comparable across all groups. Posterior eye segment scoring was normal. The drug product was stable over the study duration. No delayed toxic occurrences after recovery. IOP was in normal range for all animals.

 

Conclusions

 

OTX-DP is a biodegradable punctum plug capable of delivering dexamethasone for up to one month for the treatment of ocular inflammation. OTX-DP at an elevated dose was evaluated in beagles. Results demonstrated ocular and systemic safety when exposed to dexamethasone delivered from OTX-DP over 35 days. Findings established that the OTX-DP and insertion procedure were well tolerated in all animals.

 

 

Keywords: 445 cataract • 503 drug toxicity/drug effects • 620 ocular irritancy/toxicity testing