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A Pharmacokinetic and Safety Evaluation of an Episcleral Cyclosporine Implant for Potential Use in High-Risk Keratoplasty Rejection

¹From the National Eye Institute, the ⁴Division of Bioengineering and Physical Sciences, and the ⁶Pharmacy Department, Clinical Center, National Institutes of Health, Bethesda, Maryland; the ²Departments of Bioengineering and ³Chemical and Biomolecular Engineering, University of Maryland, College Park, Maryland; the ⁵College of Veterinary Medicine, North Carolina State University, Raleigh, North Carolina; and the ⁷Emmes Corp., Rockville, Maryland.

PURPOSE. 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 µg/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 µg/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.

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