Preclinical evaluation of a novel episcleral cyclosporine implant for ocular graft-versus-host disease

Hyuncheol Kim, Karl G. Csaky, Brian C. Gilger, James P. Dunn, Susan S. Lee, Marcus Tremblay, Francisco De Monasterio, Ginger Tansey, Peng Yuan, Peter M. Bungay, Robert J. Lutz, Michael R. Robinson

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)655-662
Number of pages8
JournalInvestigative Ophthalmology and Visual Science
Volume46
Issue number2
DOIs
StatePublished - Feb 2005

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Graft vs Host Disease
Cyclosporine
Lacrimal Apparatus
Keratoconjunctivitis Sicca
Hematopoietic Stem Cell Transplantation
Rabbits
Canidae
Dogs
Electroretinography
Eye Diseases
Silicones
Drug Delivery Systems
Tears
Pharmaceutical Preparations
Toxicology
Oral Administration
Pharmacokinetics
Morbidity

ASJC Scopus subject areas

  • Ophthalmology

Cite this

Kim, H., Csaky, K. G., Gilger, B. C., Dunn, J. P., Lee, S. S., Tremblay, M., ... Robinson, M. R. (2005). Preclinical evaluation of a novel episcleral cyclosporine implant for ocular graft-versus-host disease. Investigative Ophthalmology and Visual Science, 46(2), 655-662. https://doi.org/10.1167/iovs.04-1076

Preclinical evaluation of a novel episcleral cyclosporine implant for ocular graft-versus-host disease. / Kim, Hyuncheol; Csaky, Karl G.; Gilger, Brian C.; Dunn, James P.; Lee, Susan S.; Tremblay, Marcus; De Monasterio, Francisco; Tansey, Ginger; Yuan, Peng; Bungay, Peter M.; Lutz, Robert J.; Robinson, Michael R.

In: Investigative Ophthalmology and Visual Science, Vol. 46, No. 2, 02.2005, p. 655-662.

Research output: Contribution to journalArticle

Kim, H, Csaky, KG, Gilger, BC, Dunn, JP, Lee, SS, Tremblay, M, De Monasterio, F, Tansey, G, Yuan, P, Bungay, PM, Lutz, RJ & Robinson, MR 2005, 'Preclinical evaluation of a novel episcleral cyclosporine implant for ocular graft-versus-host disease', Investigative Ophthalmology and Visual Science, vol. 46, no. 2, pp. 655-662. https://doi.org/10.1167/iovs.04-1076
Kim, Hyuncheol ; Csaky, Karl G. ; Gilger, Brian C. ; Dunn, James P. ; Lee, Susan S. ; Tremblay, Marcus ; De Monasterio, Francisco ; Tansey, Ginger ; Yuan, Peng ; Bungay, Peter M. ; Lutz, Robert J. ; Robinson, Michael R. / Preclinical evaluation of a novel episcleral cyclosporine implant for ocular graft-versus-host disease. In: Investigative Ophthalmology and Visual Science. 2005 ; Vol. 46, No. 2. pp. 655-662.
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AU - Tremblay, Marcus

AU - De Monasterio, Francisco

AU - Tansey, Ginger

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AU - Lutz, Robert J.

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AB - 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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