- 作者：Pravin U. Dugel ; MD<sup>1sup><sup> ; sup><sup>pdugel@gmail.comsup> ; Mark S. Blumenkranz ; MD<sup>2sup> ; Julia A. Haller ; MD<sup>3sup> ; George A. Williams ; MD<sup>4sup> ; Wayne A. Solley ; MD<sup>5sup> ; David M. Kleinman ; MD<sup>6sup> ; Joel Naor ; MD<sup>7sup>
- 刊名：Ophthalmology
- 出版年：2012
- 出版时间：January 2012
- 年：2012
- 卷：119
- 期：1
- 页码：124-131
- 全文大小：489 K
ss=""h4"">Objective
To evaluate the safety and tolerability of a single subconjunctival (SCJ) or intravitreal (IVT) injection of an ophthalmic sirolimus formulation in eyes with diabetic macular edema (DME).ss=""h4"">Design
Randomized, open-label, dose-escalating phase I study.
ss=""h4"">Participants
Fifty eyes among 50 patients with DME, retinal thickness ?00 microns and best-corrected visual acuity (BCVA) 20/40 to 20/200.
ss=""h4"">Methods
A single dose of sirolimus administered SCJ (220, 440, 880, 1320, or 1760 ¦Ìg) or IVT (44, 110, 176, 264, or 352 ¦Ìg) on day 0; observation through day 90.
ss=""h4"">Main Outcome Measures
Primary end points were the frequency and severity of ocular and systemic adverse events. Secondary end points were changes in BCVA and retinal thickness.
ss=""h4"">Results
No dose-limiting toxicities were observed and ocular adverse events were mostly mild and transient. Conjunctival hyperemia, hemorrhage, and edema were common after the SCJ injection procedure and conjunctival hemorrhage was common after the IVT injection procedure. Three patients experienced ocular adverse events considered possibly related to study drug: Conjunctival edema and reduced visual acuity were reported in 1 SCJ patient each and iritis was reported in 1 IVT patient. No serious ocular adverse events were reported. No nonocular adverse events were considered related to study drug. Systemic exposure to sirolimus was low, with blood concentrations below levels necessary for systemic immunosuppression. For the SCJ group (n = 25), a median increase in BCVA started at day 7 (5.0 letters) and was 3.0, 4.0, and 4.0 letters at days 14, 45 and 90, respectively. At day 45, median decrease in retinal thickness was ?3.7 ¦Ìm. For the IVT group (n = 25), the median increase in BCVA was 2.0 letters at day 7; at days 14, 45, and 90, the median increase was maintained (4.0 letters); the median decrease in retinal thickness was ?2.0 ¦Ìm at day 45.
ss=""h4"">Conclusions
Locally administered sirolimus was well-tolerated with minimal systemic exposure at all doses tested in this small phase I population. These findings support advancing the present sirolimus formulation into phase II studies.
ss=""h4"">Financial Disclosure(s)
Proprietary or commercial disclosure may be found after the references.