Abstract
Purpose :
To evaluate the ocular and systemic toxicity and toxicokinetics of a single bilateral administration of ENV905 in rabbits. ENV905 is being developed as a treatment for inflammation and pain associated with ocular surgery.
Methods :
Male and female NZW rabbits (3/sex/group/terminal time point) were administered a single bilateral intracameral administration of ENV905 (up to 3 implants/eye) or placebo and were followed for up to 6 weeks. Animals were evaluated for standard toxicology endpoints as well as ophthalmic examinations, intraocular pressure (IOP), corneal thickness, electroretinography (ERG), plasma bioanalysis, and histopathology, and were sacrificed on Days 2 or 43.
Results :
There were no adverse test-article related effects on mortality, clinical observations, food consumption, body weights, slit lamp and indirect ophthalmoscopy, IOP, corneal thickness, or macroscopic findings at necropsy. Animals given ENV905 displayed a decrease in procedure-associated ocular inflammation on Days 2 and 3 compared with control. Mild and reversible clinical pathology and systemic histopathology findings were consistent with glucocorticoid administration. Ocular histopathology findings were limited to a decrease in ocular mixed cell inflammation and heterophilic infiltrates compared with control on Day 2, demonstrating a dampening effect on inflammation associated with the dosing procedure. Plasma concentration of desacetyl difluprednate (DFB) peaked at 2 hours post-dose in all ENV905 groups, with mean Cmax=2.5 ng/mL in the high dose group, and was not quantifiable after Day 4.
Conclusions :
A single bilateral intracameral administration of ENV905 was well tolerated in the NZW rabbit over 6 weeks, and systemic exposure to DFB was minimal. Test article-related findings were limited to mild effects associated with glucocorticoids as well as a dampening of inflammation associated with the dosing procedure. The no observed adverse effect level (NOAEL) for ENV905 in this GLP study was the high dose of 3 implants/eye.
This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.