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

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.

[1]  Hyuncheol Kim,et al.  Controlled drug release from an ocular implant: an evaluation using dynamic three-dimensional magnetic resonance imaging. , 2004, Investigative ophthalmology & visual science.

[2]  C. Johnsson,et al.  Effects of commonly used immunosuppressants on graft‐derived fibroblasts , 2004, Clinical and experimental immunology.

[3]  A. Barrett,et al.  Topical corticosteroid therapy for cicatricial conjunctivitis associated with chronic graft-versus-host disease , 2004, Bone Marrow Transplantation.

[4]  Q. Nguyen.  Avoiding and managing complications of glaucoma drainage implants , 2004, Current opinion in ophthalmology.

[5]  Jennifer L Davis,et al.  Novel approaches to ocular drug delivery. , 2004, Current opinion in molecular therapeutics.

[6]  A. Havryk,et al.  Everolimus and mycophenolate mofetil are potent inhibitors of fibroblast proliferation after lung transplantation1 , 2004, Transplantation.

[7]  Linda A. Lee,et al.  Pathogenesis and treatment of graft-versus-host disease after bone marrow transplant. , 2003, Annual review of medicine.

[8]  R. Collins,et al.  Chronic graft-vs-host disease. , 2003, JAMA.

[9]  K. Yamazaki,et al.  Periductal area as the primary site for T-cell activation in lacrimal gland chronic graft-versus-host disease. , 2003, Investigative ophthalmology & visual science.

[10]  J. Urban,et al.  The effect of hydration and matrix composition on solute diffusion in rabbit sclera. , 2000, Experimental eye research.

[11]  G. Jaffe,et al.  Long-term effect on the equine eye of an intravitreal device used for sustained release of cyclosporine A. , 2000, Veterinary ophthalmology.

[12]  Ivana K. Kim,et al.  Diffusion of high molecular weight compounds through sclera. , 2000, Investigative ophthalmology & visual science.

[13]  P. Simoens,et al.  Bilateral prolapse of the deep gland of the third eyelid in a rabbit: diagnosis and treatment. , 1999, Laboratory animal science.

[14]  S. Ding,et al.  Distribution of cyclosporin A in ocular tissues after topical administration to albino rabbits and beagle dogs. , 1999, Current eye research.

[15]  C. Ponticelli.  Optimization of cyclosporine therapy in renal transplantation. , 1998, Transplantation proceedings.

[16]  R. Yee,et al.  The use of topical cyclosporin A in ocular graft-versus-host-disease , 1998, Bone Marrow Transplantation.

[17]  Morton B. Brown,et al.  Role of intestinal P‐glycoprotein (mdr1) in interpatient variation in the oral bioavailability of cyclosporine , 1997, Clinical pharmacology and therapeutics.

[18]  J. Kreuter.  Ocular therapeutics and drug delivery , 1997 .

[19]  P. A. Pearson,et al.  Evaluation of a delivery system providing long-term release of cyclosporine. , 1996, Archives of ophthalmology.

[20]  R. Peiffer,et al.  Models in Ophthalmology and Vision Research , 1994, The Biology of the Laboratory Rabbit.

[21]  R. Kaswan,et al.  A new perspective on canine keratoconjunctivitis sicca. Treatment with ophthalmic cyclosporine. , 1990, The Veterinary clinics of North America. Small animal practice.

[22]  D. Benezra,et al.  Ocular penetration of cyclosporine A in the rat eye. , 1990, Archives of ophthalmology.

[23]  B. Kahan,et al.  Optimization of cyclosporine therapy in renal transplantation by a pharmacokinetic strategy. , 1988, Transplantation.

[24]  D. B. Feldman,et al.  Necropsy Guide: Rodents and the Rabbit , 1988 .

[25]  R. Baker.  Controlled Release of Biologically Active Agents , 1987 .

[26]  Martin Cl,et al.  Keratoconjunctivitis sicca: immunological evaluation of 62 canine cases. , 1985 .

[27]  K. Sullivan,et al.  Ocular manifestations of graft-v-host disease. , 1983, Archives of ophthalmology.

[28]  R. Fahien,et al.  Fundamentals of Transport Phenomena , 1983 .

[29]  W. Green,et al.  The eye in bone marrow transplantation. II. Histopathology. , 1983, Archives of ophthalmology.

[30]  B. S. Winkler.  Relative inhibitory effects of ATP depletion, ouabain and calcium on retinal photoreceptors. , 1983, Experimental eye research.

[31]  A. Bill,et al.  Cholinergic vasoconstrictor effects in the rabbit eye: vasomotor effects of pentobarbital anesthesia. , 1980, Acta physiologica Scandinavica.

[32]  B. S. Winkler,et al.  The electroretinogram of the isolated rat retina. , 1972, Vision research.

[33]  A. Bill.  MOVEMENT OF ALBUMIN AND DEXTRAN THROUGH THE SCLERA. , 1965, Archives of ophthalmology.

[34]  J. W. Evans,et al.  Anatomy and Histology of the Eye and Orbit in Domestic Animals. , 1961 .

[35]  Sugar Hs,et al.  The bulbar conjunctival lymphatics and their clinical significance. , 1957, Transactions - American Academy of Ophthalmology and Otolaryngology. American Academy of Ophthalmology and Otolaryngology.

[36]  K. Tsubota,et al.  Dry eye associated with chronic graft-versus-host disease. , 2002, Advances in experimental medicine and biology.

[37]  K. Tsubota,et al.  A significant role of stromal fibroblasts in rapidly progressive dry eye in patients with chronic GVHD. , 2001, Investigative ophthalmology & visual science.

[38]  M. Prausnitz,et al.  Fiber matrix model of sclera and corneal stroma for drug delivery to the eye , 1998 .

[39]  V. Rajtová,et al.  A colour atlas of the anatomy of small laboratory animals. , 1992 .

[40]  Y. Pouliquen,et al.  Ocular distribution of cyclosporin A (Sandimmun) following systemic and topical administration to rabbits. , 1991, European journal of drug metabolism and pharmacokinetics.

[41]  R. Langer,et al.  Polyanhydrides as drug delivery systems , 1990 .

[42]  R. Langer,et al.  Biodegradable polymers as drug delivery systems , 1990 .

[43]  K. Masuda,et al.  Water flow in Tenon's capsule and subconjunctival tissue of rabbit. , 1984, Japanese journal of ophthalmology.

[44]  S. Weisbroth,et al.  The Biology of the Laboratory Rabbit , 1974 .

[45]  A. Alm,et al.  Ocular and optic nerve blood flow at normal and increased intraocular pressures in monkeys (Macaca irus): a study with radioactively labelled microspheres including flow determinations in brain and some other tissues. , 1973, Experimental eye research.

[46]  John Crank,et al.  The Mathematics Of Diffusion , 1956 .