Pharmacokinetic and Toxicity Study of an Intraocular Cyclosporine DDS in the Anterior Segment of Rabbit Eyes

Abstract

PURPOSE. To establish the safety and pharmacokinetic efficacy of an Oculex Drug Delivery System (DDS; Oculex Pharmaceuticals, Inc., Sunnyvale, CA) containing cyclosporin A (CsA) in the anterior segment of the rabbit eye. METHODS. The Oculex DDS is an intraocular, sustained-release, drug delivery system comprising a biodegradable lactic acid-glycolic acid copolymer. A controlled prospective study was performed that involved implanting a DDS containing 0.5 mg of CsA into the anterior chamber (AC) of the right eyes of 16 New Zealand White rabbits. A placebo DDS was implanted into the left eyes of these same rabbits as the control. Slit lamp examinations and AC taps were performed serially, and the rabbits were killed and the globes removed at 2, 4, 8, and 12 weeks for histology and determination of CsA drug levels. Analysis of CsA levels was performed with high-performance liquid chromatography-mass spectrometry. RESULTS. High concentrations of CsA were detectable in all layers of the cornea (epithelium, corneal stroma and endothelium) throughout the 3-month period. Low CsA levels were detected in the aqueous, whereas no CsA was detectable in the blood. There were no adverse reactions observed. CONCLUSIONS. The Oculex DDS CsA device is effective in delivering long-term levels of CsA to corneal tissues, without adverse effects. Further studies in an animal model of corneal transplant rejection should be performed to determine the potential of this device in the prophylaxis and treatment of corneal transplant rejection in humans.