A Low Concentration of Tacrolimus/Semifluorinated Alkane (SFA)Eyedrop Suppresses Intraocular Inflammation in ExperimentalModels of Uveitis

Purpose: Corticosteroids remain the mainstay therapy for uveitis, a majorcause of blindness in the working age population. However, a substantial number ofpatients cannot benefit from the therapy due to steroids resistance or intolerance.Tacrolimus has been used to treat refractory uveitis through systemic administration. Theaim of this study was to evaluate the therapeutic potential of 0.03% tacrolimus eyedropin mouse models of uveitis.Methods: 0.03% tacrolimus in perfluorobutylpentane (F4H5) (0.03% Tacrolimus/SFA)was formulated using a previously published protocol. Tacrolimus suspended in PBS(0.03% Tacrolimus/PBS) was used as a control. In addition, 0.1% dexamethasone (0.1%DXM) was used as a standard therapy control. Endotoxin-induced uveitis (EIU) andexperimental autoimmune uveoretinitis (EAU) were induced in adult C57BL/6 mice usingprotocols described previously. Mice were treated with eyedrops three times/dayimmediately after EIU induction for 48 h or from day 14 to day 25 post-immunization (forEAU). Clinical and histological examinations were conducted at the end of theexperiment. Pharmacokinetics study was conducted in mice with and without EIU. Atdifferent times after eyedrop treatment, ocular tissues were collected for tacrolimusmeasurement.Results: The 0.03% Tacrolimus/SFA eyedrop treatment reduced the clinical scores andhistological scores of intraocular inflammation in both EIU and EAU to the levels similarto 0.1% DXM eyedrop treatment. The 0.03% Tacrolimus/PBS did not show anysuppressive effect in EIU and EAU. Pharmacokinetic studies showed that 15 min aftertopical administration of 0.03% Tacrolimus/SFA, low levels of tacrolimus were detectedin the retina (48 ng/g tissue) and vitreous (2.5 ng/ml) in normal mouse eyes, and thelevels were significantly higher in EIU eyes (102 ng/g tissue in the retina and 24 ng/ml inthe vitreous). Tacrolimus remained detectable in intraocular tissues of EIU eyes 6 h aftertopical administration (68 ng/g retinal tissue, 10 ng/ml vitreous). Only background levelsof tacrolimus were detected in the retina (2-8 ng/g tissue) after 0.03% Tacrolimus/PBSeyedrop administration.Conclusion: 0.03% Tacrolimus/SFA eyedrop can penetrate ocular barrier and reachintraocular tissue at therapeutic levels in mouse eyes, particularly under inflammatoryconditions. 0.03% Tacrolimus/SFA eyedrop may have therapeutic potentials forinflammatory eye diseases including uveitis.