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Yasir Jamal Sepah, Diana V Do, Hitomi Takanaga, Sreenivasu Mudumba, Quan Dong Nguyen; Pharmacokinetics of Sirolimus in Subjects Treated with Intravitreal Sirolimus in the SAVE-2 Study: Sirolimus As Therapeutic Approach to UVEitis – Protocol 2 with Two Doses of Intravitreal Sirolimus. Invest. Ophthalmol. Vis. Sci. 2018;59(9):415. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
To determine the blood and aqueous humor levels of intravitreal (IVT) sirolimus among subjects in SAVE-2, a clinical trial with repeated administrations of study drug.
SAVE-2 randomizes up to 32 subjects with intermediate, posterior, or pan-uveitis of non-infectious etiology to receiving IVT sirolimus in study eyes of either 440 µg monthly (at baseline/BL, month/M 1, 2, 3, 4, 5) or 880 µg bimonthly (at BL, M 2, 4). After primary endpoint at M6 and until end of study at M12, subjects were treated with IVT sirolimus on as needed basis based on retreatment criteria.Whole blood (WB) and aqueous humor (AH) were collected at BL, M3, 6, 10,12 in the SAVE-2 Study. Sirolimus concentrations in WB and AH following IVT injection were evaluated using liquid chromatography–tandem mass spectrometry (LC-MS/MS). Blood samples were collected in tubes containing K3 EDTA. Sirolimus was extracted from WB and AH by lysis/extraction/protein precipitation, solid-phase extraction and extracts were subsequently analyzed by LC-MS/MS. Lower Limit of Quantification (LLOQ) are at 0.25 ng/mL (WB) and 2.5 ng/mL (AH). BLQ (Below of lower quantification) is defined as <0.25 ng/mL for WB and <2.5 ng/mL for AH.
At least 4 and up to 9 WB or AH samples were available for each analysis. In WB, the LLOQ is at 0.25 ng/mL. For 440 µg, pharmacokinetics (PK) levels of sirolimus were BLQ at all measured timepoints. For 880 µg, PK level of sirolimus remained close to BLQ at various timepoints, except at M3, when levels were > BLQ. As a reference, for systemic immunosuppressive effect of sirolimus, a trough state WB concentration of approximately 10 ng/mL is required.In AH, the LLOQ is at 2.5 ng/mL. For 440 µg, PK levels of sirolimus were BLQ at all measured timepoints in AH. For 880 µg, at the timepoints measured, maximum levels of sirolimus were observed at M3.
Preliminary results of PK analyses in the SAVE-2 Study suggest that there may be a dose-associated detection of sirolimus as the levels of sirolimus were higher with IVT 880 µg dosing in both WB and AH among treated subjects. Overall, with repeated IVT administrations of sirolimus (440 µg monthly or 880 µg bimonthly), there is absence of sirolimus or presence at level much below immunosuppression in whole blood.
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.
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