Evaluation of a delivery system providing long-term release of cyclosporine

Objectives: To examine the clearance of cyclosporine after intravitreal injection and to assess the kinetics and toxic effects of an intravitreal device that provides sustained delivery of cyclosporine. Methods: Rabbits were divided into two groups to evaluate (1) the elimination kinetics after 1-mu g and 10-mu g intravitreal injections of cyclosporine and (2) the levels produced after implantation of a device that contained cyclosporine over 6 months. The toxic effects of the intravitreal device over 6 months were assessed in rabbits and cynomolgus monkeys. Results: After the 10-mu g injection, the half-life was longer (10.8 hours vs 4.2 hours) and the distribution volume was smaller (1.7 mL vs 3.2 mL) than after the 1-mu g injection. This difference can be attributed to saturable partitioning of the drug. The device resulted in a vitreous concentration of approximately 500 ng/mL throughout the study period. In the rabbit it resulted in reversible lens opacification and decreased b-wave amplitude. This toxic effect was not detected in the monkey. Conclusions: The device produces sustained intravitreal levels of cyclosporine. Although it was associated with reversible toxic effects in the rabbit, it was well tolerated in primates. Sustained-release implants are a promising new treatment for chronic uveitis.