Evaluation of a delivery system providing long-term release of cyclosporine.
OBJECTIVE
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-microgram and 10-microgram 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-microgram 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-microgram 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.
Pearson
P A
PA
Department of Ophthalmology, Duke University, Durham, NC, USA.
Jaffe
G J
GJ
Martin
D F
DF
Cordahi
G J
GJ
Grossniklaus
H
H
Schmeisser
E T
ET
Ashton
P
P
D000818:Animals; D001682:Biological Availability; D002386:Cataract / Q000139:chemically induced / Q000503:physiopathology; D016572:Cyclosporine / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity; D003692:Delayed-Action Preparations; D016503:Drug Delivery Systems; D004341:Drug Evaluation; D004343:Drug Implants; D004596:Electroretinography; D005123:Eye / Q000378:metabolism; D005260:Female; D006207:Half-Life; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity; D007267:Injections; D007908:Lens, Crystalline / Q000187:drug effects / Q000378:metabolism; D008252:Macaca fascicularis; D008297:Male; D011817:Rabbits; D012160:Retina / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D014018:Tissue Distribution; D014822:Vitreous Body / Q000378:metabolism*
D003692:Delayed-Action Preparations; D004343:Drug Implants; D007166:Immunosuppressive Agents; D016572:Cyclosporine