June 2015
Volume 56, Issue 7
Free
ARVO Annual Meeting Abstract  |   June 2015
Pharmacokinetics of Intravitreal Sirolimus in Non-infectious Uveitis (NIU) of the Posterior Segment: Results from a Subset of SAKURA Study 1 Subjects
Author Affiliations & Notes
  • Daniel Rosberger
    MaculaCare, New York, NY
  • Yang Yang
    Santen, Inc., Emeryville, CA
  • Masaaki Kageyama
    Santen Ltd., Osaka, Japan
  • Hidetoshi Mano
    Santen Ltd., Osaka, Japan
  • Hitomi Takenaga
    Santen Ltd., Osaka, Japan
  • Kenji Ueda
    Santen Ltd., Osaka, Japan
  • Lisa Lawrence-Miyasaki
    Santen, Inc., Emeryville, CA
  • Footnotes
    Commercial Relationships Daniel Rosberger, None; Yang Yang, Santen, Inc. (E); Masaaki Kageyama, Santen Ltd. (E); Hidetoshi Mano, Santen Ltd. (E); Hitomi Takenaga, Santen Ltd. (E); Kenji Ueda, Santen Ltd. (E); Lisa Lawrence-Miyasaki, Santen, Inc. (E)
  • Footnotes
    Support None
Investigative Ophthalmology & Visual Science June 2015, Vol.56, 3114. doi:
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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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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract
 
Purpose
 

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.

 
Methods
 

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.

 
Results
 

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.

 
Conclusions
 

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.  

 
Figure 1. Mean±SD sirolimus concentrations in human blood following bimonthly intravitreal sirolimus injections.
 
Figure 1. Mean±SD sirolimus concentrations in human blood following bimonthly intravitreal sirolimus injections.

 
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