title: A novel water-soluble cyclosporine A prodrug: ocular tolerance and in vivo kinetics.
abstract: The purpose of this study is to demonstrate that a novel water-soluble prodrug of cyclosporine A (CsA) intended for topical ocular administration, does not induce eye irritation in a rabbit model and is able to generate therapeutic concentrations of CsA in the precorneal area immediately after administration. The eye irritancy of the prodrug and CsA control solution was assessed by the Draize test and by confocal laser ophthalmoscopy (CLSO). Residence time and tear concentrations of prodrug and CsA in the rabbit eye were assessed by HPLC. The Draize test showed an excellent tolerance for the prodrug solution while the reference CsA oil solution induced lachrymation and irritation. The CLSO-measured corneal lesions, subsequent to treatment with the prodrug and reference solutions, were 3% and 9%, respectively. The prodrug transformed rapidly, leading to relatively stable CsA concentrations in tears with a maximal concentration of 94 microg ml(-1) over the observation period. This study demonstrated that the prodrug solution was well tolerated and that clinically significant CsA tear concentrations were achieved. UNIL088 is a promising molecule in the treatment of immune-related disorders of the eye.
authors.affiliation: Laboratory of Pharmaceutical Technology and Biopharmaceutics, School of Pharmacy, University of Geneva, 1211 Geneva 4, Switzerland.
authors.forename: F
authors.initials: F
authors.lastname: Lallemand
authors.forename: P
authors.initials: P
authors.lastname: Furrer
authors.forename: O
authors.initials: O
authors.lastname: Felt-Baeyens
authors.forename: M
authors.initials: M
authors.lastname: Gex-Fabry
authors.forename: J-M
authors.initials: JM
authors.lastname: Dumont
authors.forename: K
authors.initials: K
authors.lastname: Besseghir
authors.forename: R
authors.initials: R
authors.lastname: Gurny
mesh_terms: D000287:Administration, Topical; D000818:Animals; D016572:Cyclosporine / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity; D004361:Drug Tolerance; D005123:Eye / Q000187:drug effects; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics*; D008297:Male; D011355:Prodrugs / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity; D011817:Rabbits; D013666:Tears / Q000378:metabolism
chemical_list: D007166:Immunosuppressive Agents; D011355:Prodrugs; D016572:Cyclosporine