A pharmacokinetic and safety evaluation of an episcleral cyclosporine implant for potential use in high-risk keratoplasty rejection.
OBJECTIVE
To determine the short and long-term pharmacokinetics and assess the toxicity of a cyclosporine (CsA) episcleral implant for the prevention of high-risk keratoplasty rejection.


METHODS
CsA episcleral implants were made with a high (implant A) or low (implant B) release rate, and in vitro release rates were performed. Short-term pharmacokinetics were performed in rabbits using implant B, and the spatial and temporal spread of drug was observed by sampling from multiple corneal and conjunctival sites at 3 and 72 hours. Implant A was used in long-term pharmacokinetic studies in dogs aged more than 1 year. An ocular toxicity study was performed in dogs older than 1 year.


RESULTS
A high release rate was observed with both implants over the initial 5 months followed by a steady state release. The cumulative release over the 400-day assay period from implants A and B was 3.8 +/- 0.3 and 2.3 +/- 0.3 mg, respectively. In the short-term pharmacokinetic studies, the cornea had CsA concentrations of 0.15 +/- 0.06, 0.07 +/- 0.02, and 0.05 +/- 0.02 microg/mg at sites centered 8, 13, and 18 mm away from the implant site, respectively. In the long-term pharmacokinetic studies, corneal CsA levels ranged from 0.18 +/- 0.06 to 0.009 +/- 0.004 microg/mg during the 1-year study. There were no signs of ocular toxicity at 1 year.


CONCLUSIONS
Episcleral implants are safe and effective at delivering therapeutic CsA levels to the cornea to potentially prevent corneal allograft rejection. The implant can be surgically inserted at the time of penetrating keratoplasties, since the implant achieves therapeutic levels as early as 3 hours.
Lee
Susan S
SS
National Eye Institute, Clinical Center, National Institutes of Health, Bethesda, Maryland 20892, USA. susan.sh.lee@gmail.com
Kim
Hyuncheol
H
Wang
Nam Sun
NS
Bungay
Peter M
PM
Gilger
Brian C
BC
Yuan
Peng
P
Kim
Jonghyeon
J
Csaky
Karl G
KG
Robinson
Michael R
MR
D000818:Animals; D001082:Aqueous Humor / Q000378:metabolism; D001682:Biological Availability; D003228:Conjunctiva / Q000378:metabolism; D003315:Cornea / Q000378:metabolism*; D016572:Cyclosporine / Q000493:pharmacokinetics* / Q000633:toxicity; D004285:Dogs; D004343:Drug Implants; D005143:Eyelids / Q000378:metabolism; D005260:Female; D006084:Graft Rejection / Q000517:prevention & control*; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics* / Q000633:toxicity; D015948:Keratoplasty, Penetrating; D008198:Lymph Nodes / Q000378:metabolism; D008297:Male; D011817:Rabbits; D012590:Sclera / Q000378:metabolism*
D004343:Drug Implants; D007166:Immunosuppressive Agents; D016572:Cyclosporine