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Daniel Rosberger, Yang Yang, Masaaki Kageyama, Hidetoshi Mano, Hitomi Takenaga, Kenji Ueda, Lisa Lawrence-Miyasaki, ; Pharmacokinetics of Intravitreal Sirolimus in Non-infectious Uveitis (NIU) of the Posterior Segment: Results from a Subset of SAKURA Study 1 Subjects. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):3114.
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Optimally, an intraocular medication for NIU of the posterior segment should have minimal systemic concentrations to avoid systemic adverse effects, with no drug accumulation. Intravitreal sirolimus is a locally delivered mTOR inhibitor that is currently being studied in the Phase III SAKURA trial as monotherapy for the treatment of active NIU of the posterior segment. Here, we describe the whole-blood pharmacokinetics of intravitreal sirolimus in the subset of subjects from Japan (n=14) who participated in SAKURA Study 1.
In the 6-month, double-masked phase of SAKURA Study 1, subjects received intravitreal sirolimus injections of 44, 440, or 880 μg at Months 0, 2, and 4. Blood samples were taken at baseline and on Days 1, 3, 14, 30, 60 (before and after the second injection), 62, 73, 90, 120 (after the third injection), 122, 133, and 150, and at Month 6. Blood sirolimus concentrations were determined by liquid chromatography/tandem mass spectrometry.
Following the first injection, blood sirolimus concentrations rapidly increased, reaching a Cmax of 0.337, 1.97, and 3.06 ng/mL at a mean Tmax of 0.69, 1.3, and 4.2 days for the 44, 440, and 880 µg doses, respectively. Sirolimus concentrations gradually declined toward the limit of quantitation level within 30 days after the injection. The corresponding mean AUC0-60d at doses of 44, 440, and 880 µg were 1.5, 15.0, and 30.5 ng∙day/mL, respectively. The same pattern was observed after the second and third injections (see Figure 1). The mean Cmax and AUC0-60d did not change between the first and the third administration with any dose, suggesting that there was no systemic accumulation of sirolimus after repeated intravitreal injections.
In this subset of Japanese subjects from SAKURA Study 1, mean sirolimus concentrations remained well below the 5-15 ng/mL considered necessary for systemic immunosuppression throughout the entire study period, indicating that systemic exposure to sirolimus after repeated intravitreal injections is negligible. This finding, together with the low incidence of systemic adverse events in SAKURA Study 1, indicates that the effects of intravitreal sirolimus are confined to the eye.
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