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Cyclosporine--ocular absorption, pharmacokinetics & effects on uveitis

University of British Columbia

Inflammatory ocular disease is an important cause of blindness and uveitis accounts for 1.0% of blind patients in Canada.¹ This disease can be particularly troublesome to treat, because the nature of the causal factor or factors and mechanisms of progressi n are usually unknown. Non-specific anti - inflammatory agents have been used orally and systemically with some success to treat uveitis, ²⁻⁸ but they may produce serious side effects both locally and elsewhere in the body.⁹̛¹²̛¹⁴ With prolonged use tolerance to these drugs may develop , making them ineffective. Recently a powerful immuno suppressive agent, Cyclosporine (Cy), used orally and systemically in the treatment of uveitis has shown promising results.¹⁶⁻¹⁹̛²⁸ However, its routine use is limited because of a narrow therapeutic index and renal toxicity. Several studies have shown that subconjunctival injection of a number of antineoplastic agents enhanced ocular absorption ²⁰⁻²⁴ in a traditional pharmacological sanctuary,¹³̛¹⁴ and circumvented the associated systemic side effects. Therefore, if Cy were administered subconjunctivally it might be possible to avoid the side effects associated with the oral and systemic routes, and at the same time provide higher levels of Cy to the eye. A protocol for the administration of Cy subconjunctivally was developed in New Zealand white rabbits, to study toxicity, ocular pharmacokinetics following equidose administration subconjunctivally and systemically and the effects of Cy on an animal model of uveitis. Subconjuntival administration of 5mg of Cy in O.lcc (Sandimmune I.V.(R) 50 mg/ml) weekly was found to be the maximum tolerated dose by the rabbitsˈ eye, and was superior to intravenous injection for ocular penetration while minimizing systemic exposure. The uveitis model showed that Cy was effective in reducing the inflammatory response and the earlier the application of Cy the milder the uveitis. The results from our study support the contention that local administration of Cy would lead to higher levels of Cy absorption and circumvent the side effects of systemic administration. This may facilitate the routine use of Cy in ocular inflammatory disease.

Text

2010-07-14

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http://hdl.handle.net/2429/26422

Pathology

University of British Columbia

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