PMID- 30060978
OWN - NLM
STAT- MEDLINE
DCOM- 20190916
LR  - 20220408
IS  - 1549-4713 (Electronic)
IS  - 0161-6420 (Linking)
VI  - 125
IP  - 12
DP  - 2018 Dec
TI  - Intravitreal Sirolimus for the Treatment of Noninfectious Uveitis: Evolution 
      through Preclinical and Clinical Studies.
PG  - 1984-1993
LID - S0161-6420(17)33538-8 [pii]
LID - 10.1016/j.ophtha.2018.06.015 [doi]
AB  - In recent decades, the treatment paradigm for noninfectious intermediate uveitis, 
      posterior uveitis, and panuveitis, a group of intraocular inflammatory diseases, 
      has included systemic and local (periocular or intraocular) corticosteroids, 
      biologics, and other steroid-sparing immunomodulatory therapy agents. Recently, 
      an intravitreal formulation of sirolimus, an immunosuppressant that inhibits the 
      mammalian target of rapamycin, a key regulator of cell growth in the immune 
      system, was developed. On the basis of this mechanism and the local method of 
      delivery, it was hypothesized that intravitreal sirolimus can improve ocular 
      inflammation in patients with noninfectious intermediate uveitis, posterior 
      uveitis, and panuveitis, with minimal systemic exposure and systemic adverse 
      events (AEs). This review summarizes the pharmacokinetics, efficacy, and safety 
      results of intravitreal sirolimus from 3 preclinical studies and 4 phase 1-3 
      clinical studies. Preclinical studies in rabbits showed that 22 to 220 mug 
      intravitreal sirolimus results in sustained release of sirolimus in the vitreous 
      for 2 months or more, with systemic concentrations below the threshold for 
      systemic immunosuppression (approximately 8 ng/ml). Subsequently, 2 phase 1 
      studies (n = 50 and n = 30) established that intravitreal sirolimus improves 
      ocular inflammation in humans. Further investigation in phase 2 and 3 studies 
      (n = 24 and n = 347, respectively) suggested that 440 mug has the best 
      benefit-to-risk profile. In the phase 3 study, the proportion of patients who 
      showed complete resolution of ocular inflammation at month 5 was significantly 
      higher in the 440-mug group than in the 44-mug group (22.8% vs. 10.3%; P = 0.025, 
      Fisher exact test). In addition, 47 of 69 patients (68.1%) who were treated with 
      systemic corticosteroids at baseline discontinued corticosteroid use at month 5. 
      No sirolimus-related systemic AEs were reported in phase 1-3 studies. 
      Collectively, these preclinical and clinical study data of intravitreal sirolimus 
      support the therapeutic rationale of treating noninfectious uveitis with a local 
      mammalian target of rapamycin inhibitor and suggest that 440 mug intravitreal 
      sirolimus has the potential to be an effective and well-tolerated 
      anti-inflammatory and corticosteroid-sparing treatment for noninfectious 
      intermediate uveitis, posterior uveitis, and panuveitis.
CI  - Copyright (c) 2018 American Academy of Ophthalmology. Published by Elsevier Inc. 
      All rights reserved.
FAU - Nguyen, Quan Dong
AU  - Nguyen QD
AD  - Byers Eye Institute, Stanford University School of Medicine, Palo Alto, 
      California. Electronic address: ndquan@stanford.edu.
FAU - Merrill, Pauline T
AU  - Merrill PT
AD  - Department of Ophthalmology, Rush University Medical Center, Chicago, Illinois.
FAU - Sepah, Yasir J
AU  - Sepah YJ
AD  - Byers Eye Institute, Stanford University School of Medicine, Palo Alto, 
      California.
FAU - Ibrahim, Mohamed A
AU  - Ibrahim MA
AD  - Wilmer Eye Institute, Johns Hopkins University, Baltimore, Maryland; Ocular 
      Imaging Research and Reading Center (OIRRC), Menlo Park, California.
FAU - Banker, Alay
AU  - Banker A
AD  - Banker's Retina Clinic and Laser Center, Navrangpura, Ahmedabad, India.
FAU - Leonardi, Andrea
AU  - Leonardi A
AD  - Department of Neuroscience, Ophthalmology Unit, University of Padua, Padua, 
      Italy.
FAU - Chernock, Michelle
AU  - Chernock M
AD  - Santen, Inc., Emeryville, California.
FAU - Mudumba, Sri
AU  - Mudumba S
AD  - Santen, Inc., Emeryville, California.
FAU - Do, Diana V
AU  - Do DV
AD  - Byers Eye Institute, Stanford University School of Medicine, Palo Alto, 
      California.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Review
DEP - 20180727
PL  - United States
TA  - Ophthalmology
JT  - Ophthalmology
JID - 7802443
RN  - 0 (Immunosuppressive Agents)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Animals
MH  - Clinical Trials as Topic
MH  - Drug Evaluation, Preclinical
MH  - Humans
MH  - Immunosuppressive Agents/*therapeutic use
MH  - Intravitreal Injections
MH  - Panuveitis/*drug therapy
MH  - Sirolimus/*therapeutic use
MH  - Uveitis, Intermediate/*drug therapy
MH  - Uveitis, Posterior/*drug therapy
EDAT- 2018/08/01 06:00
MHDA- 2019/09/17 06:00
CRDT- 2018/08/01 06:00
PHST- 2017/11/30 00:00 [received]
PHST- 2018/05/31 00:00 [revised]
PHST- 2018/06/11 00:00 [accepted]
PHST- 2018/08/01 06:00 [pubmed]
PHST- 2019/09/17 06:00 [medline]
PHST- 2018/08/01 06:00 [entrez]
AID - S0161-6420(17)33538-8 [pii]
AID - 10.1016/j.ophtha.2018.06.015 [doi]
PST - ppublish
SO  - Ophthalmology. 2018 Dec;125(12):1984-1993. doi: 10.1016/j.ophtha.2018.06.015. 
      Epub 2018 Jul 27.