{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,4]],"date-time":"2026-05-04T15:48:13Z","timestamp":1777909693145,"version":"3.51.4"},"reference-count":22,"publisher":"SAGE Publications","issue":"5","license":[{"start":{"date-parts":[[2012,6,4]],"date-time":"2012-06-04T00:00:00Z","timestamp":1338768000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Journal of Ocular Pharmacology and Therapeutics"],"published-print":{"date-parts":[[2012,10,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Purpose:<\/jats:title>\n                    <jats:p>To evaluate the pharmacokinetics (PK) and tolerability of a proprietary sirolimus depot-forming ocular formulation in rabbits and humans after a single intravitreal (IVT) injection.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods:<\/jats:title>\n                    <jats:p>New Zealand White (NZW) rabbits were intravitreally injected in both eyes with an injectable formulation in 5 (3 PK and 2 tolerability) studies. The rabbits received up to approximately 220\u2009\u03bcg sirolimus per eye. At the desired timing post-injection, the animals were euthanized; both eyes were enucleated, frozen, and dissected to separate sclera, retina\/choroid, and vitreous humor (VH). Whole blood (WB) samples were obtained at each time point before euthanasia. In clinical trials, patients received an IVT injection of approximately 352\u2009\u03bcg sirolimus. Sirolimus concentrations in ocular tissues and WB samples were measured using liquid chromatography\/tandem mass spectrometry (LC\/MS\/MS). In both single- and repeat-dose tolerability studies, systemic and ocular adverse effects were evaluated.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results:<\/jats:title>\n                    <jats:p>\n                      After IVT administration, sirolimus formed a depot in the VH. During dissolution, concentrations in VH were dose related and exhibited continuous release from the depot. This was characterized by a gradient of sirolimus concentration in the order of VH &gt; retina\/choroid &gt; sclera &gt; WB, and the concentrations were maintained for approximately 2 months after the IVT injection. After repeat dosing (132\u2009\u03bcg), no drug accumulation was seen in the ocular tissue or systemically. In clinical studies, the highest blood levels were &lt;2\u2009ng\/mL at day 2, and half-time (\n                      <jats:italic toggle=\"yes\">t<\/jats:italic>\n                      <jats:sub>1\/2<\/jats:sub>\n                      ) was 8\u20139 days. There was no accumulation at day 30 after the IVT injection (up to 352\u2009\u03bcg). Safety studies conducted on rabbits indicated good local tolerability. Sirolimus-related effects were limited to minor incipient cataract findings and mild lenticular changes. In the clinical studies where sirolimus was intravitreally administered up to 352\u2009\u03bcg, injections were well tolerated.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions:<\/jats:title>\n                    <jats:p>Sustained IVT delivery was achieved in a dose-dependent fashion after the IVT injection of a proprietary sirolimus depot-forming ocular formulation. Across the tolerability and safety studies, no significant findings were observed for systemic and ocular tolerability. The human WB levels were well below the daily trough systemic blood level range required for systemic immunosuppression. An IVT injection of sirolimus has a PK and safety profile that is favorable for treating inflammatory conditions of the eye, such as non-infectious uveitis, and warrants further investigation in humans.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1089\/jop.2011.0226","type":"journal-article","created":{"date-parts":[[2012,6,5]],"date-time":"2012-06-05T02:15:35Z","timestamp":1338862535000},"page":"507-514","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":30,"title":["Tolerability and Pharmacokinetics of Intravitreal Sirolimus"],"prefix":"10.1177","volume":"28","author":[{"given":"Sri","family":"Mudumba","sequence":"first","affiliation":[{"name":"Santen Incorporated"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Padma","family":"Bezwada","sequence":"additional","affiliation":[{"name":"Santen Incorporated"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hitomi","family":"Takanaga","sequence":"additional","affiliation":[{"name":"Santen Incorporated"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kazuhiro","family":"Hosoi","sequence":"additional","affiliation":[{"name":"Santen Pharmaceutical Co., Ltd.","place":["Japan"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Takashi","family":"Tsuboi","sequence":"additional","affiliation":[{"name":"Santen Pharmaceutical Co., Ltd.","place":["Japan"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kenji","family":"Ueda","sequence":"additional","affiliation":[{"name":"Santen Pharmaceutical Co., Ltd.","place":["Japan"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kouichi","family":"Kawazu","sequence":"additional","affiliation":[{"name":"Santen Pharmaceutical Co., Ltd.","place":["Japan"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yusuf","family":"Ali","sequence":"additional","affiliation":[{"name":"Santen Incorporated"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joel","family":"Naor","sequence":"additional","affiliation":[{"name":"Santen Incorporated"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"179","published-online":{"date-parts":[[2012,6,4]]},"reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1517\/13543784.16.10.1525"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1089\/10807680151125537"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1136\/bjo.2004.048199"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1007\/s12348-010-0015-5"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1097\/00007691-200110000-00012"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0009-9120(98)00045-9"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1167\/iovs.04-0753"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1097\/00007691-199512000-00019"},{"key":"e_1_3_2_10_2","volume-title":"Rapamune (sirolimus) Oral Solution and Tablets, approval in 1999","unstructured":"Rapamune (sirolimus) Oral Solution and Tablets, approval in 1999. 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