Clinical Pharmacokinetics

, Volume 44, Issue 3, pp 247–261 | Cite as

Ocular Pharmacokinetics and Safety of Ciclosporin, a Novel Topical Treatment for Dry Eye

Review Article


Ciclosporin is a potent immunomodulator that acts selectively and locally when administered at the ocular surface. 0.05% ciclosporin ophthalmic emulsion has recently been approved by the US FDA for treatment of keratoconjunctivitis sicca (KCS) [dry-eye disease].

After topical application, ciclosporin accumulates at the ocular surface and cornea, achieving concentrations (≥0.236 μg/g) that are sufficient for immunomodulation. Very little drug penetrates through the ocular surface to intraocular tissues. Ciclosporin is not metabolised in rabbit or dog eyes and may not be prone to metabolism in human eyes. Cultured human corneal endothelial and stromal cells exposed to ciclosporin in vitro exhibited no adverse effects and only minor effects on DNA synthesis. No ocular or systemic toxicity was seen with long-term ocular administration of ciclosporin at concentrations up to 0.4%, given as many as six times daily for 6 months in rabbits and 1 year in dogs. Systemic blood ciclosporin concentration after ocular administration was extremely low or undetectable in rabbits, dogs and humans, obviating concerns about systemic toxicity. In 12-week and 1-year clinical safety studies in dry-eye patients, the most common adverse event associated with the ophthalmic use of ciclosporin emulsion was ocular burning. No serious drug-related adverse events occurred.

These data from in vitro, nonclinical and clinical studies indicate effective topical delivery of ciclosporin to desired target tissues along with a favourable safety profile, making 0.05% ciclosporin ophthalmic emulsion a promising treatment for KCS.


Ocular Surface Lacrimal Gland Keratoconjunctivitis Sicca Ocular Administration Herpetic Stromal Keratitis 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



The authors are employees of Allergan Inc., manufacturer of Restasis™. This article is a scientific review of published literature.


  1. 1.
    Faulds D, Goa KL, Benfield P. Cyclosporin: a review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in immunoregulatory disorders. Drugs 1993; 45: 953–1040PubMedCrossRefGoogle Scholar
  2. 2.
    DeBakey ME. Cyclosporin A: a new era in organ transplantation. Compr Ther 1984; 10: 7–15PubMedGoogle Scholar
  3. 3.
    Nussenblatt RB, Palestine AG, Chan CC, et al. Randomized, double-masked study of cyclosporine compared to prednisolone in the treatment of endogenous uveitis. Am J Ophthalmol 1991; 112: 138–46PubMedGoogle Scholar
  4. 4.
    Dick AD, Azim M, Forrester JV. Immunosuppressive therapy for chronic uveitis: optimising therapy with steroids and cyclosporin A. Br J Ophthalmol 1997; 81: 1107–12PubMedCrossRefGoogle Scholar
  5. 5.
    Ozdal PC, Ortac S, Taskintuna I, et al. Long-term therapy with low dose cyclosporin A in ocular Behcet’s disease. Doc Ophthalmol 2002; 105: 301–12PubMedCrossRefGoogle Scholar
  6. 6.
    Masuda K, Nakajima A, Urayama A, et al. Double-masked trial of cyclosporin versus colchicine and long-term open study of cyclosporin in Behcet’s disease. Lancet 1989; I: 1093–6CrossRefGoogle Scholar
  7. 7.
    Le Hoang P, Girard B, Deray G, et al. Cyclosporine in the treatment of birdshot retinochoroidopathy. Transplant Proc 1988; 20: 128–30PubMedGoogle Scholar
  8. 8.
    Binder AI, Graham EM, Sanders MD, et al. Cyclosporin A in the treatment of severe Behcet’s uveitis. Br J Rheumatol 1987; 26: 285–91PubMedCrossRefGoogle Scholar
  9. 9.
    Oh C, Apel AJ, Saville BA, et al. Local efficacy of cyclosporine in corneal transplant therapy. Curr Eye Res 1994; 13: 337–43PubMedCrossRefGoogle Scholar
  10. 10.
    Ben Ezra D, Matamoros N, Cohen E. Treatment of severe vernal keratoconjunctivitis with cyclosporine A eyedrops. Transplant Proc 1988; 20: 644–9Google Scholar
  11. 11.
    Calonge M. The treatment of dry eye. Surv Ophthalmol 2001; 45 Suppl. 2: S227–39PubMedCrossRefGoogle Scholar
  12. 12.
    Kiang E, Tesavibul N, Yee R, et al. The use of topical cyclosporin A in ocular graft-versus-host-disease. Bone Marrow Transplant 1998; 22: 147–51PubMedCrossRefGoogle Scholar
  13. 13.
    Diaz-Valle D, Benitez del Castillo JM, Castillo A, et al. Immunologic and clinical evaluation of postsurgical necrotizing sclerocorneal ulceration. Cornea 1998; 17: 371–5PubMedCrossRefGoogle Scholar
  14. 14.
    Gunduz K, Ozdemir O. Topical cyclosporin as an adjunct to topical acyclovir treatment in herpetic stromal keratitis. Ophthalmic Res 1997; 29: 405–8PubMedCrossRefGoogle Scholar
  15. 15.
    Sall K, Stevenson OD, Mundorf TK, et al. Two multicenter, randomized studies of the efficacy and safety of cyclosporine ophthalmic emulsion in moderate to severe dry eye disease. CsA Phase 3 Study Group. Ophthalmology 2000; 107: 631–9PubMedCrossRefGoogle Scholar
  16. 16.
    Stevenson D, Tauber J, Reis BL. Efficacy and safety of cyclosporin A ophthalmic emulsion in the treatment of moderate-to-severe dry eye disease: a dose-ranging, randomized trial. The Cyclosporin A Phase 2 Study Group. Ophthalmology 2000; 107: 967–74PubMedCrossRefGoogle Scholar
  17. 17.
    Stern ME, Geo J, Siemasko KF, et al. Role of the lacrimal gland functional unit in the pathophysiology of dry eye. Exp Eye Res 2004; 78: 409–16PubMedCrossRefGoogle Scholar
  18. 18.
    Pepose JS, Akata RF, Pflugfelder SC, et al. Mononuclear cell phenotypes and immunoglobulin gene rearrangements in lacrimal gland biopsies from patients with Sjogren’s syndrome. Ophthalmology 1990; 97: 1599–605PubMedGoogle Scholar
  19. 19.
    Pflugfelder SC, Wilhelmus KR, Osato MS, et al. The autoimmune nature of aqueous tear deficiency. Ophthalmology 1986; 93: 1513–7PubMedGoogle Scholar
  20. 20.
    Borel JF, Baumann G, Chapman I, et al. In vivo pharmacological effects of ciclosporin and some analogues. Adv Pharmacol 1996; 35: 115–246PubMedCrossRefGoogle Scholar
  21. 21.
    Drosos AA, Skopouli FN, Costopoulos JS, et al. Cyclosporin A (CyA) in primary Sjogren’s syndrome: a double blind study. Ann Rheum Dis 1986; 45: 732–5PubMedCrossRefGoogle Scholar
  22. 22.
    Laibovitz RA, Solch S, Andriano K, et al. Pilot trial of cyclosporine 1% ophthalmic ointment in the treatment of keratoconjunctivitis sicca. Cornea 1993; 12: 315–23PubMedCrossRefGoogle Scholar
  23. 23.
    Power WJ, Mullaney P, Farrell M, et al. Effect of topical cyclosporin A on conjunctival T cells in patients with secondary Sjogren’s syndrome. Cornea 1993; 12: 507–11PubMedCrossRefGoogle Scholar
  24. 24.
    Fox RI, Tornwall J, Maruyama T, et al. Evolving concepts of diagnosis, pathogenesis, and therapy of Sjogren’s syndrome. Curr Opin Rheumatol 1998; 10: 446–56PubMedCrossRefGoogle Scholar
  25. 25.
    Kaswan RL, Salisbury MA, Ward DA. Spontaneous canine keratoconjunctivitis sicca: a useful model for human keratoconjunctivitis sicca: treatment with cyclosporine eye drops. Arch Ophthalmol 1989; 107: 1210–6PubMedCrossRefGoogle Scholar
  26. 26.
    Kaswan RL, Salisbury MA. A new perspective on canine keratoconjunctivitis sicca: treatment with ophthalmic cyclosporine. Vet Clin North Am Small Anim Pract 1990; 20: 583–613PubMedGoogle Scholar
  27. 27.
    Morgan RV, Abrams KL. Topical administration of cyclosporine for treatment of keratoconjunctivitis sicca in dogs. J Am Vet Med Assoc 1991; 199: 1043–6PubMedGoogle Scholar
  28. 28.
    Olivero DK, Davidson MG, English RV, et al. Clinical evaluation of 1% cyclosporine for topical treatment of keratoconjunctivitis sicca in dogs. J Am Vet Med Assoc 1991; 199: 1039–42PubMedGoogle Scholar
  29. 29.
    Wiederholt M, Kossendrup D, Schulz W, et al. Pharmacokinetic of topical cyclosporin A in the rabbit eye. Invest Ophthalmol Vis Sci 1986; 27: 519–24PubMedGoogle Scholar
  30. 30.
    Kanai A, Alba RM, Takano T, et al. The effect on the cornea of alpha cyclodextrin vehicle for cyclosporin eye drops. Transplant Proc 1989; 21: 3150–32PubMedGoogle Scholar
  31. 31.
    Reidy JJ, Gebhardt BM, Kaufman HE. The collagen shield: a new vehicle for delivery of cyclosporin A to the eye. Cornea 1990; 9: 196–9PubMedCrossRefGoogle Scholar
  32. 32.
    Calvo P, Sanchez A, Martinez J, et al. Polyester nanocapsules as new topical ocular delivery systems for cyclosporin A. Pharm Res 1996; 13: 311–5PubMedCrossRefGoogle Scholar
  33. 33.
    De Campos AM, Sanchez A, Alonso MJ. Chitosan nanoparticles: a new vehicle for the improvement of the delivery of drugs to the ocular surface: application to cyclosporin A. Int J Pharm 2001; 224: 159–68PubMedCrossRefGoogle Scholar
  34. 34.
    Gebhardt BM, Kaufman HE. Collagen as a delivery system for hydrophobic drugs: studies with cyclosporine. J Ocul Pharmacol Ther 1995; 11: 319–27PubMedCrossRefGoogle Scholar
  35. 35.
    Borel JF. CsA: historical perspectives. Transplant Proc 1983; 15: 2219–29Google Scholar
  36. 36.
    Secchi AG, Tognon MS, Leonardi A. Topical use of cyclosporine in the treatment of vernal keratoconjunctivitis. Am J Ophthalmol 1990; 110: 641–5PubMedGoogle Scholar
  37. 37.
    Bonduelle S, Foucher C, Leroux JC, et al. Association of cyclosporin to isohexylcyanoacrylate nanospheres and subsequent release in human plasma in vitro. J Microencapsul 1992; 9: 173–82PubMedCrossRefGoogle Scholar
  38. 38.
    Bonduelle S, Carrier M, Pimienta C, et al. Tissue concentration of nanoencapsulated radio-labelled cyclosporin following peroral delivery in mice or ophthalmic application to rabbits. Eur J Pharm Biopharm 1996; 42: 313–9Google Scholar
  39. 39.
    Belin MW, Bouchard CS, Frantz S, et al. Topical cyclosporine in high-risk corneal transplants. Ophthalmology 1989; 96: 1144–50PubMedGoogle Scholar
  40. 40.
    Restasis™ prescribing information. Irvine (CA): Allergan Inc., 2003Google Scholar
  41. 41.
    Acheampong AA, Shackleton M, Tang-Liu D, et al. Distribution of cyclosporin A in ocular tissues after topical administration to albino rabbits and beagle dogs. Curr Eye Res 1999; 18: 91–103PubMedCrossRefGoogle Scholar
  42. 42.
    Snibson GR, Greaves JL, Soper ND, et al. Precorneal residence times of sodium hyaluronate solutions studied by quantitative gamma scintigraphy. Eye 1990; 4(Pt 4): 594–602PubMedCrossRefGoogle Scholar
  43. 43.
    Bethem R, Lehman J, Woolley P, et al. Quantitative analysis of cyclosporin A in human whole blood by LC-API/MS/MS. Pharm Res 1999; 14: S–698Google Scholar
  44. 44.
    Kirchner GI, Vidal C, Winkler M, et al. LC/ESI-MS allows simultaneous and specific quantification of SDZ RAD and cyclosporine, including groups of their metabolites in human blood. Ther Drug Monit 1999; 21: 116–22PubMedCrossRefGoogle Scholar
  45. 45.
    Schroeder TJ, Brunson ME, Pesce AJ, et al. A comparison of the clinical utility of the radioimmunoassay, high-performance liquid chromatography, and TDx cyclosporine assays in outpatient renal transplant recipients. Transplantation 1989; 47: 262–6PubMedCrossRefGoogle Scholar
  46. 46.
    Simpson J, Zhang Q, Ozaeta P, et al. A specific method for the measurement of cyclosporin A in human whole blood by liquid chromatography-tandem mass spectrometry. Ther Drug Monit 1998; 20: 294–300PubMedCrossRefGoogle Scholar
  47. 47.
    Steimer W. Performance and specificity of monoclonal immunoassays for cyclosporine monitoring: how specific is specific? Clin Chem 1999; 45: 371–81PubMedGoogle Scholar
  48. 48.
    Zucchelli GC, Pilo A, Chiesa MR, et al. Progress report of an external quality assessment scheme for cyclosporine assay. Ther Drug Monit 1996; 18: 273–9PubMedCrossRefGoogle Scholar
  49. 49.
    Kaswan RL. Intraocular penetration of topically applied cyclosporine. Transplant Proc 1988; 20: 650–5PubMedGoogle Scholar
  50. 50.
    Mosteller MW, Gebhardt BM, Hamilton AM, et al. Penetration of topical cyclosporine into the rabbit cornea, aqueous humor, and serum. Arch Ophthalmol 1985; 103: 101–2PubMedCrossRefGoogle Scholar
  51. 51.
    Bellot JL, Alio JL, Ruiz Moreno JM, et al. Corneal concentration and systemic absorption of cyclosporin-A following its topical application in the rabbit eye. Ophthalmic Res 1992; 24: 351–6PubMedCrossRefGoogle Scholar
  52. 52.
    Ben Ezra D, Maftzir G. Ocular penetration of cyclosporin A: the rabbit eye. Invest Ophthalmol Vis Sci 1990; 31: 1362–6Google Scholar
  53. 53.
    Foets B, Missotten L, Vanderveeren P, et al. Prolonged survival of allogeneic corneal grafts in rabbits treated with topically applied cyclosporin A: systemic absorption and local immunosuppressive effect. Br J Ophthalmol 1985; 69: 600–3PubMedCrossRefGoogle Scholar
  54. 54.
    Study report PK-98-074. Ocular cyclosporine distribution during 91/2 days of dosing of 0.05% and 0.1% 3H-cyclosporin A emulsion to albino rabbit eyes. Irvine (CA): Allergan, 1998. (Data on file)Google Scholar
  55. 55.
    Study report PK-99-073. Cornea, conjunctiva and aqueous humor concentrations in rabbits and dogs dosed every 15 minutes four times with an aqueous formulation of 0.5% 3H-cyclosporine. Irvine (CA): Allergan, 1999. (Data on file)Google Scholar
  56. 56.
    Study report PK-98-016. Ocular absorption and disposition in beagle dogs following multiple ocular doses of 0.2% 3H-cyclosporine emulsion. Irvine (CA): Allergan, 1996. (Data on file)Google Scholar
  57. 57.
    Acheampong AA, Shackleton M, Lam S, et al. Cyclosporine distribution into the conjunctiva, cornea, lacrimal gland, and systemic blood following topical dosing of cyclosporine to rabbit, dog, and human eyes. Adv Exp Med Biol 1998; 438: 1001–4PubMedCrossRefGoogle Scholar
  58. 58.
    Study report PK-96-011. Dose proportionality of ocular tissue 3H-cyclosporine concentrations after a single dose administration of 0.05%, 0.2% and 0.4% cyclosporine emulsions into rabbit eyes. Irvine (CA): Allergan, 1996. (Data on file)Google Scholar
  59. 59.
    Theng J, Zhiou L, Tan D, et al. Distribution of cyclosporine A in the cornea after topical or oral administration. J Ocular Pharmacol Ther 2002; 18: 83–8CrossRefGoogle Scholar
  60. 60.
    Althaus C, Dagres E, Reinhard T, et al. Cyclosporin-A and its metabolites in the anterior chamber after topical and systemic application as determined with high-performance liquid chromatography-electrospray mass spectrometry. Ger J Ophthalmol 1996; 5: 189–94PubMedGoogle Scholar
  61. 61.
    Perry HD, Donnenfeld ED, Acheampong A, et al. Topical cyclosporine A in the management of postkeratoplasty glaucoma and corticosteroid-induced ocular hypertension (CIOH) and the penetration of topical 0.5% cyclosporine A into the cornea and anterior chamber. CLAO J 1998; 24: 159–65PubMedGoogle Scholar
  62. 62.
    Pfau B, Kruse FE, Rohrschneider K, et al. Comparison between local and systemic administration of cyclosporin A on the effective level in conjunctiva, aqueous humor and serum [in German]. Ophthalmologe 1995; 92: 833–9PubMedGoogle Scholar
  63. 63.
    Chipont E, Diaz-Llopis M, Tomas S, et al. Collagen shields and intraocular penetration of cyclosporin. Arch Soc Esp Oftalmol 1995; 69: 251–7Google Scholar
  64. 64.
    Diaz-Llopis M, Menezo JL. Penetration of 2% cyclosporin eyedrops into human aqueous humour. Br J Ophthalmol 1989; 73: 600–3PubMedCrossRefGoogle Scholar
  65. 65.
    Minguez E, Tiestos MT, Cristobal JA, et al. Intraocular absorption of cyclosporin A eyedrops [in French]. J Fr Ophtalmol 1992; 15: 263–7PubMedGoogle Scholar
  66. 66.
    Vickers AE, Fischer V, Connors S, et al. Cyclosporin A metabolism in human liver, kidney, and intestine slices: comparison to rat and dog slices and human cell lines. Drug Metab Dispos 1992; 20: 802–9PubMedGoogle Scholar
  67. 67.
    Combalbert J, Fabre I, Fabre G, et al. Metabolism of cyclosporin A: IV. Purification and identification of the rifampicin-inducible human liver cytochrome P-450 (cyclosporin A oxidase) as a product of P450IIIA gene subfamily. Drug Metab Dispos 1989; 17: 197–207PubMedGoogle Scholar
  68. 68.
    Madhu C, Dinh D, Babusis D, et al. Expression of cytochrome P450 isoenzymes in dog and human eye. Proceedings of the 9th Annual North American ISSX Meeting; 1999 Oct 24–28; Nashville. Bethesda (MD): ISSX 1999; 15: 162Google Scholar
  69. 69.
    Sandborn WJ, Lawson GM, Krom RA, et al. Hepatic allograft cyclosporine concentration is independent of the route of cyclosporine administration and correlates with the occurrence of early cellular rejection. Hepatology 1992; 15: 1086–91PubMedCrossRefGoogle Scholar
  70. 70.
    Hanas E, Tufveson G, Lindgren PG, et al. Concentration of cyclosporin-A and its metabolites in transplanted human kidney tissue during rejection and stable graft function. Clin Transplant 1991; 5: 107–11Google Scholar
  71. 71.
    Sandborn WJ, Tremaine WJ, Lawson GM. Clinical response does not correlate with intestinal or blood cyclosporine concentrations in patients with Crohn’s disease treated with highdose oral cyclosporine. Am J Gastroenterol 1996; 91: 37–43PubMedGoogle Scholar
  72. 72.
    Sandborn WJ, Tremaine WJ, Schroeder KW, et al. Cyclosporine enemas for treatment-resistant, mildly to moderately active, left-sided ulcerative colitis. Am J Gastroenterol 1993; 88: 640–5PubMedGoogle Scholar
  73. 73.
    Physician’s desk reference. Montvale (NJ): Medical Economics, 2002: 2388-91Google Scholar
  74. 74.
    Singh G, Lindstrom RL, Doughman DJ. Cyclosporin A on human corneal endothelium. Cornea 1984; 3: 272–7PubMedCrossRefGoogle Scholar
  75. 75.
    Ben Ezra D, Antebe I, Maftzir G. Differential effect of cyclosporin A on lymphocyte and keratocyte proliferation [abstract]. Invest Ophthalmol Vis Sci 1987; 28: 42Google Scholar
  76. 76.
    Angelov O, Wiese A, Yuan Y, et al. Preclinical safety studies of cyclosporine ophthalmic emulsion. Adv Exp Med Biol 1998; 438: 991–5PubMedCrossRefGoogle Scholar
  77. 77.
    Salisbury MA, Kaswan RL, Brown J. Effect of topical cyclosporine on the recovery of micro-organisms from dogs with KCS [abstract]. Invest Ophthalmol Vis Sci 1994; 35: 1693Google Scholar
  78. 78.
    Ryffel B. The carcinogenicity of ciclosporin. Toxicology 1992; 73: 1–22PubMedCrossRefGoogle Scholar
  79. 79.
    Donatsch P, Ryffel B. Pharmacokinetics of cyclosporine in toxicological studies. Transplant Proc 1986; 6: 71–6Google Scholar
  80. 80.
    Study report PK-00-013. Cyclosporine A concentrations in the eyes of rats and dogs dosed orally with cyclosporin A for 5 days. Irvine (CA): Allergan, 2000. (Data on file)Google Scholar
  81. 81.
    de Vries J, Baarsma GS, Zaal MJ, et al. Cyclosporin in the treatment of severe chronic idiopathic uveitis. Br J Ophthalmol 1990; 74: 344–9PubMedCrossRefGoogle Scholar
  82. 82.
    Cohen E, Raz J, Maftzir G, et al. Low-dose cyclosporin A in uveitis. Ocul Immunol Inflamm 1993; 1: 195–201PubMedCrossRefGoogle Scholar
  83. 83.
    Towler HM, Lightman SL, Forrester JV. Low-dose cyclosporin therapy of ocular inflammation: preliminary report of a long-term follow-up study. J Autoimmun 1992; 5 Suppl. A: 259–64PubMedCrossRefGoogle Scholar
  84. 84.
    Towler HM, Whiting PH, Forrester JV. Combination low dose cyclosporin A and steroid therapy in chronic intraocular inflammation. Eye 1990; 4(Pt 3): 514–20PubMedCrossRefGoogle Scholar
  85. 85.
    Towler HM, Cliffe AM, Whiting PH, et al. Low dose cyclosporin A therapy in chronic posterior uveitis. Eye 1989; 3(Pt 3): 282–7PubMedCrossRefGoogle Scholar
  86. 86.
    Nussenblatt RB, Palestine AG, Chan CC. Cyclosporine therapy for uveitis: long-term followup. J Ocul Pharmacol 1985; 1: 369–82PubMedCrossRefGoogle Scholar
  87. 87.
    Small DS, Acheampong A, Reis B, et al. Blood concentrations of cyclosporin a during long-term treatment with cyclosporin a ophthalmic emulsions in patients with moderate to severe dry eye disease. J Ocul Pharmacol Ther 2002; 18: 411–8PubMedCrossRefGoogle Scholar

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© Adis Data Information BV 2005

Authors and Affiliations

  1. 1.Department of Pharmacokinetics and Drug MetabolismAllergan, Inc.IrvineUSA

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