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Sri Mudumba, Hitomi Takanaga, Padma Bezwada, Laura Wilson, Joel Naor; Intravitreal Administration of Ocular Formulation of Sirolimus in Rabbits and Humans. Invest. Ophthalmol. Vis. Sci. 2012;53(14):3198.
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To evaluate the pharmacokinetics of a proprietary sirolimus depot-forming ocular formulation (DE-109; currently in clinical trials for posterior uveitis. www.clinicaltrials.gov; NCT01358266) in rabbits and humans following a single intravitreal (IVT) injection.
New Zealand White (NZW) rabbits were injected intravitreally in both eyes with the formulation. Sixty-three animals were divided into 3 groups receiving either 22, 66, or 220 μg sirolimus per eye. At 3, 7, 14, 29, 62, 90 and 162 days post-injection, 3 animals/group were euthanized, both eyes enucleated, frozen and dissected to separate retina/choroid and vitreous humor (VH). 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 Age-related Macular Degeneration (AMD), 10 patients received an IVT injection in one eye of 352 μg sirolimus bimonthly (NCT 00712491). Whole blood samples were collected at similar time points for quantification of sirolimus concentration using LC/MS/MS.
Intravitreal delivery of DE-109 in NZW rabbits following a single IVT injection was characterized by a gradient of sirolimus concentration in the order of VH >retina/choroid >sclera >whole blood with detectable ocular tissue levels extending 60 days. Three days post-injection of 220 μg per eye (440 μg total), mean sirolimus concentrations of 390, 1.6, 0.01 and 0.004 μg/(g or mL) were detected in VH, retina/choroid, sclera, 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-life (t1/2) of 7 to 8 days. Whole blood sirolimus concentrations in AMD patients injected intravitreally appeared to follow similar kinetics (t1/2; 8-9 days). The highest sirolimus levels were shown at Day 2 and were <2 ng/mL. There was no accumulation 30 days after injection.
After IVT administration of DE-109, the formation of a depot in the VH that dissolves over time, allows extended availability of sirolimus to ocular tissues with low and transient systemic exposure.
Clinical Trial: :
http://www.clinicaltrials.gov NCT 00712491
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