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(Investigative Ophthalmology and Visual Science. 2005;46:655-662.)
© 2005 by The Association for Research in Vision and Ophthalmology, Inc.
DOI:  10.1167/iovs.04-1076
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Preclinical Evaluation of a Novel Episcleral Cyclosporine Implant for Ocular Graft-Versus-Host Disease

Hyuncheol Kim,1 Karl G. Csaky,1 Brian C. Gilger,2 James P. Dunn,3 Susan S. Lee,1 Marcus Tremblay,1 Francisco de Monasterio,1 Ginger Tansey,1 Peng Yuan,4 Peter M. Bungay,5 Robert J. Lutz,5 and Michael R. Robinson1

1From the National Eye Institute, National Institutes of Health, Bethesda, Maryland; the 2College of Veterinary Medicine, North Carolina State University, Raleigh, North Carolina; 3Wilmer Eye Institute, Johns Hopkins Hospital, Baltimore, Maryland; the 4Pharmacy Department, Clinical Center, and the 5Division of Bioengineering and Physical Sciences, National Institutes of Health, Bethesda, Maryland.

PURPOSE. To develop a local drug delivery system that provides therapeutic cyclosporine levels to treat lacrimal gland graft-versus-host disease after allogeneic hematopoietic stem cell transplantation.

METHODS. Episcleral cyclosporine implants were manufactured with a silicone-based matrix design, and in vitro release rates were determined. Preclinical evaluation included toxicology (clinical examination, serial electroretinography, and histopathology) in normal rabbits and dogs, pharmacokinetics in normal rabbits, and pharmacodynamics in a canine model of aqueous tear deficiency and keratoconjunctivitis sicca.

RESULTS. The cyclosporine implants showed sustained release of drug over time with in vitro assays. Histopathology showed normal ocular tissues in both dogs and rabbits 6 months after implantation. The cyclosporine implant produced lacrimal gland drug levels 1 to 2 log units higher than those reported with a variety of topical cyclosporine formulations and oral administration. The cyclosporine implant was effective in a canine model of keratoconjunctivitis sicca, with all animals able to discontinue topical cyclosporine and maintain normal Schirmer scores over a 6-month follow-up.

CONCLUSIONS. This preclinical evaluation showed that the episcleral cyclosporine implant was safe, delivered potentially therapeutic cyclosporine levels to the lacrimal gland, and showed efficacy in a clinically relevant model of keratoconjunctivitis sicca. The episcleral cyclosporine implant shows promise in reducing the morbidity associated with lacrimal gland graft-versus-host disease after allogeneic hematopoietic stem cell transplantation. In addition, continuous release of cyclosporine in the subconjunctival space with the episcleral implant was an effective means of delivering drug to the ocular surface and may have potential in treating other ocular inflammatory diseases.




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