EVALUATION OF A DELIVERY SYSTEM PROVIDING LONG-TERM RELEASE OF CYCLOSPORINE

Objectives: To examine the clearance of cyclosporine after intravitrea l injection and to assess the kinetics and toxic effects of an intravi treal 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 cyclospo rine and (2) the levels produced after implantation of a device that c ontained cyclosporine over 6 months. The toxic effects of the intravit real device over 6 months were assessed in rabbits and cynomolgus monk eys. Results: After the 10-mu g injection, the half-life was longer (1 0.8 hours vs 4.2 hours) and the distribution volume was smaller (1.7 m L vs 3.2 mL) than after the 1-mu g injection. This difference can be a ttributed to saturable partitioning of the drug. The device resulted i n a vitreous concentration of approximately 500 ng/mL throughout the s tudy period. In the rabbit it resulted in reversible lens opacificatio n and decreased b-wave amplitude. This toxic effect was not detected i n the monkey. Conclusions: The device produces sustained intravitreal levels of cyclosporine. Although it was associated with reversible tox ic effects in the rabbit, it was well tolerated in primates. Sustained -release implants are a promising new treatment for chronic uveitis.