Evaluation of Octreotide / ATRIGEL® Sustained Release Formulation Administered Intravitreally or in the Sub–Tenon Space in the Rabbit

Abstract

Purpose: : Octreotide, a long–acting octapeptide with pharmacologic actions similar to the natural hormone, somatostatin, is a potential therapy for retinal and choroidal neovascularization. A polymeric, biodegradable in situ–forming implant (ATRIGEL, QLT USA, Inc., Fort Collins, CO) was developed for the sustained release of octreotide. We report here on the tolerance of the implants administered intravitreally or in the sub–tenon space in the rabbit eye and the release of octreotide to the posterior segment.

Methods: : A 12% octreotide /ATRIGEL formulation that displayed a 90–day release profile in subcutaneous tissue and the equivalent blank ATRIGEL formulation or saline were administered intravitreally or in the sub–tenon space in New Zealand White rabbits. Tolerance was assessed by monitoring intraocular pressure and by ophthalmic examination up to 120 days. Eye globes were collected for histopathology at 30, 90 and 120 days after injection. Octreotide concentrations in ocular tissues and in implants retrieved at different timepoints were determined by LC–MS/MS.

Results: : In 10% of 30 eyes, subtenon injections of both the octreotide/ATRIGEL and blank ATRIGEL formulations were associated with conjunctival swelling and hyperemia that resolved after 1 week. No adverse effects were observed after intreavitreal administration, except procedure–related cataracts in less than 10% of the eyes. The octreotide/ATRIGEL formulation exhibited a 24–hour release of 18% and 22% after intravitreal and sub–tenon administration, respectively, compared to 20% after subcutaneous injection. The release rate fitted a zero–order kinetic with about 50% and 75% of octreotide released from intravitreal and subtenon implants, respectively, 45 days after injection. Biodistribution results indicated that octreotide concentrations in the retina and choroid were similar after intravitreal administration, whereas the retina concentrations were about 10 times lower than those in the choroid in eyes with subtenon implants. Complete release, biodistribution, and histopathological results will be presented.

Conclusions: : The ATRIGEL delivery system is well tolerated in the eye and can effectively deliver octreotide to the retina and choroid. The release of octreotide from intravitreal or sub–tenon implants was consistent with that observed in subcutaneous implants.

Keywords: drug toxicity/drug effects • injection • diabetic retinopathy