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T. Nivaggioli, J. X. Bao, S. Farooq, D. A. Weber, J. Naor; Pharmacokinetics of a Locally Administered Subconjunctival Ocular Formulation of Sirolimus in Rabbits and Humans. Invest. Ophthalmol. Vis. Sci. 2009;50(13):5164.
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To evaluate the pharmacokinetics of a proprietary sirolimus depot-forming ocular formulation in rabbits and humans following a single subconjunctival injection.
New Zealand White (NZW) rabbits were injected subconjunctivally in both eyes with the formulation. Fifty-four animals were divided into 3 groups receiving either 66, 220, or 660 µg sirolimus per eye. At 3, 7, 14, 29, 62, and 90 days post-injection, 3 animals/group were euthanized, both eyes enucleated, frozen and dissected to separate sclera/conjunctiva, retina/choroid and vitreous humor. Whole blood samples were obtained at each time point prior to euthanasia. Sirolimus concentrations in ocular tissues and whole blood were measured using LC/MS/MS. In a separate prospective, open-label study of chronic, refractory diabetic macular edema (DME), patients were randomized into 5 patients/group and received a subconjunctival injection in one eye of 220, 440, 880, 1320 or 1760 µg sirolimus (www.clinicaltrials.gov; NCT00401115). Whole blood samples were collected at similar time points for quantification of sirolimus concentration using LC/MS/MS.
Substantial transscleral delivery of sirolimus was achieved in NZW rabbits following a single subconjunctival injection. This was characterized by a gradient of sirolimus concentration in the order of sclera/conjunctiva>retina/choroid>vitreous humor, with detectable ocular tissue levels extending 60 to 90 days. Three days post-injection of 660 µg per eye (1320 µg total), mean sirolimus concentrations of 7518, 237, 33 ng/g and 11 ng/mL were detected in sclera/conjunctiva, retina/choroid, vitreous humor, and whole blood, respectively. There was a clear dose-dependent change in both sirolimus concentration and duration of exposure. Sirolimus concentrations declined exponentially over time, with elimination half-times (t1/2) of 6 to 7 days. Ocular tissue concentrations correlated well with systemic levels for retina/choroid, sclera/conjunctiva and vitreous humor [r2 = 0.9815 (P=0.0011), r2 = 0.9195 (P=0.0099) and r2 = 0.8597 (P=0.0233)], respectively. Whole blood sirolimus concentrations in DME patients injected subconjunctivally also appeared to be dose-related and to follow similar kinetics.
Sustained transscleral delivery was achieved in a dose-dependent fashion for 60 to 90 days following a single subconjunctival injection of a proprietary sirolimus depot-forming ocular formulation. Strong correlation was found between systemic whole blood and ocular tissue concentrations. Comparison with systemic pharmacokinetic data in humans suggests similar ocular pharmacokinetics.
Clinical Trial: :
www.clinicaltrials.gov NCT 00401115
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