Pharmacokinetics data suggests sirolimus activity confined to eye

Take-home message: Serial measurements of sirolimus blood concentrations after intravitreal injection show the maximum concentration achieved was below the level generally associated with systemic immunosuppression.

By Cheryl Guttman Krader; Reviewed by Daniel F. Rosberger, MD, PhD, MPH

New York-Pharmacokinetics data from SAKURA Study 1-the first of two phase III studies investigating intravitreal sirolimus (Santen) for the treatment of noninfectious uveitis of the posterior segment of the eye-show there is minimal systemic exposure to the immunoregulatory agent, even after repeated dosing, said Daniel F. Rosberger, MD, PhD, MPH.

“Results from analyses of primary, secondary, and exploratory endpoints in SAKURA Study 1 demonstrated the efficacy of sirolimus as a treatment for non-infectious uveitis of the posterior segment,” said Dr. Rosberger, a SAKURA principal investigator, and clinical assistant professor of ophthalmology, Weill Cornell Medical College, New York.

The findings from the pharmacokinetics analyses show that the concentrations achieved in the blood never reached the threshold required for systemic immunosuppression, Dr. Rosberger noted.

“Those results are consistent with the low incidence of systemic adverse events observed in SAKURA Study 1, and indicate that the treatment benefits observed are the result of sirolimus activity at the target site in the eye,” said Dr. Rosberger, a retina specialist in private practice, MaculaCare, New York.

SAKURA Study 1

SAKURA Study 1 was a 6-month, double-masked, randomized trial comparing sirolimus 440 and 880 mcg against sirolimus 44 mcg as an active control. Study subjects received a total of 3 intravitreal injections every 2 months during the double-masked treatment period.

The pharmacokinetics study was performed in a subset of 14 patients enrolled at 4 investigational sites in Japan. They had blood samples collected at screening and on study days 1 (post-injection), 3, 14, 30, 60, 62, 73, 90, 120, 122, 133, and 150, and 180.

On days 60 and 120, samples were taken both immediately before and immediately after intravitreal injection. Six of the 14 patients were being treated with sirolimus 440 mcg, 5 were in the 880 mcg group, and 3 were receiving the 44 mcg control dose.

Analyses by liquid chromatography/tandem mass spectrometry showed the blood concentration of sirolimus increased rapidly and in a dose-related fashion. Mean sirolimus maximum blood concentrations (C_max) achieved after administration of the 44, 440, and 880 mcg doses were 0.337, 1.97, and 3.06 ng/mL, respectively.

“The concentration of sirolimus considered necessary to cause systemic immunosuppression ranges from 5 to 15 ng/mL,” Dr. Rosberger said. “However, the concentration of sirolimus in the blood remained far below the lower limit of that level even with administration of the 880-mcg dose.”

Based on the outcomes from the SAKURA Study 1, the ongoing second pivotal trial investigating intravitreal sirolimus for the treatment of noninfectious uveitis of the posterior segment of the eye (SAKURA Study 2) is investigating the 440 mcg dose as compared with the 44-mcg dose, he noted.

Time to maximum concentration (T_max) following administration of the first injection of sirolimus ranged from <1 to ~4 days across the three treatment groups. In subjects treated with the 440-mcg dose, the mean sirolimus concentrations at Days 14 and 30 were 0.208 and 0.021 ng/mL, respectively, and it was below the level of quantitation on Day 60, before the second injection.

The C_max and T_max values after the second and third intravitreal doses were similar to those calculated after the initial injection, and the area under the blood concentration-time curve from 0 hour to Day 60 were also unchanged.

 “These data suggest there was no systemic accumulation of sirolimus with repeated dosing,” Dr. Rosberger said.

Daniel F. Rosberger, MD, PhD, MPH

E: drosberger@nyc.rr.com

This article was adapted from Dr. Rosberger’s presentation at the 2015 meeting of the Association for Research in Vision and Ophthalmology. Dr. Rosberger has no relevant financial interests to disclose.