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Masaaki Kageyama, Joel Naor, Hitomi Takanaga, Laura Wilson, Nnenna Ihekoromadu, Afsheen Khwaja, Sri Mudumba; Comparison of Pharmacokinetic profiles of Sirolimus following Subconjunctival or Intravitreal Administrations in Rabbits and Humans. Invest. Ophthalmol. Vis. Sci. 2013;54(15):5370.
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© ARVO (1962-2015); The Authors (2016-present)
To compare pharmacokinetic (PK) profiles of a proprietary sirolimus depot-forming ocular formulation (DE-109; currently in clinical trials for Posterior Uveitis. www.clinicaltrials.gov; NCT01358266) following subconjunctival (SCJ) or intravitreal (IVT) injection in rabbits and humans.
New Zealand White (NZW) rabbits were injected SCJ or IVT in both eyes with the formulation. Each group of 3 animals received one SCJ injection of 66, 220, or 660 μg/eye vs. an IVT injection of 22, 66, or 220 μg/eye, in 2 separate studies. Ocular tissues and whole blood (WB) were taken at multiple time points post-injection. Eyes were enucleated, frozen and dissected to separate ocular tissues. WB samples were obtained at each time point prior to euthanasia. sirolimus concentrations were measured using LC/MS/MS. In a separate human study of Age-related Macular Degeneration (ARMD), 10 patients received three SCJ (1320 μg) or IVT (352 μg) injection in one eye bimonthly (NCT 00712491). WB samples were collected at similar time points for quantification of sirolimus concentrations using LC/MS/MS.
SCJ delivery of sirolimus in NZW rabbits following a single injection was characterized by a distribution gradient of sirolimus concentration order: Sclera>Retina/Choroid>VH>WB. iIin contrast, IVT delivery showed ocular distribution order: VH>Retina/Choroid>Sclera>WB. 3-days post-SCJ injection of 660 μg/eye (1320 μg total), sirolimus concentrations of 14, 0.37, 0.014 and 0.01 μg/(g or mL) were detected in Sclera, Retina/Choroid, VH, and WB, respectively. 3-days post-IVT injection of 220 μg/eye (440 μg total), sirolimus concentrations of 390, 1.6, 0.01 and 0.004 μg/(g or mL) were detected in VH, Retina/Choroid, Sclera, and WB, respectively. In ARMD study, the highest sirolimus blood levels Cmax were (IVT: <2 ng/mL vs. SCJ: <10 ng/mL) at Day 2 and half-life t1/2 (IVT: 8-9 days vs. SCJ: 3-4 days).
Compared with SCJ delivery, the IVT route of administration showed an ocular distribution gradient more consistent with the intended preferential release of the drug from the depot to the retina. Both routes showed low systemic exposure.
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