Search for a command to run...
Purpose : Tacrolimus is a highly potent calcineurin inhibitor, mainly used as systemic immunosuppressant. One application of tacrolimus, albeit off-label, is orally in non-infectious uveitis. The water-free drug delivery platform EyeSol® has the potential to deliver tacrolimus to the uvea after topical administration. The use of eye drops could lead to a safe and convenient alternative to the use of high dose steroids or orally applied calcineurin inhibitors.To investigate the ocular distribution after topical ocular administration, pharmacokinetics of different tacrolimus formulations was studied in rabbits and dogs. Methods : NZW rabbits and Beagle dogs received multiple topical ocular doses of tacrolimus (as 0.03% solution or 0.03%, 0.1%, 0.3% suspension) TID for 3 days and a single dose on Day 4. Animals were then sacrificed at specific timepoints after the last dose (rabbit: 0.5h, 1h, 2h, 4h, 8h, 24h; dog: 1h, 4h). Ocular tissues were collected, and levels of tacrolimus were evaluated in aqueous humor, cornea, vitreous, bulbar and palpebral conjunctivae, iris/ciliary body, retina, RPE/choroid, sclera and blood using LC-MS/MS. Results : In both species, the highest mean concentrations of tacrolimus were observed between 0.5 and 2 hours post dose in the anterior segment of the eye, as expected for a topical treatment. Significant concentrations reached the uvea with levels well above the recommended systemic exposure for transplant rejection (10 ng/g). For the highest dose levels tested (0.03% solution and 0.3% suspension) also pharmacologically relevant retina exposure was detected in rabbit. Systemic concentrations were negligible, and all formulations were well tolerated in both studies. The comparison of different formulations showed a dose response for all three suspensions, and the 0.03% solution was comparable to the highest suspension. The tissue concentrations in rabbits were approx. 3 times higher compared to dogs, which is an expected finding considering the differences in size and anatomy of the eyes. The distribution pattern of all test articles was overall comparable. Conclusions : Repeated topical ocular dosing of tacrolimus in EyeSol® resulted in pharmacologically active levels of tacrolimus in the uvea target tissues, in both rabbit and dog. These results and published findings from in-vivo models indicate potential for tacrolimus as a topical treatment option for uveitis.