{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T15:39:21Z","timestamp":1788536361191,"version":"build-2803163510"},"reference-count":39,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2019,11,20]],"date-time":"2019-11-20T00:00:00Z","timestamp":1574208000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["bpspubs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Pharmacology Res &amp; Perspec"],"published-print":{"date-parts":[[2019,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Age\u2010related macular degeneration (AMD) is the leading cause of severe vision impairment in patients over the age of 60\u00a0years. Choroidal neovascularization (CNV) is the hallmark of neovascular AMD and vascular endothelial growth factor (VEGF) plays a causal role in the formation of CNV. Although regorafenib and pazopanib, small molecule VEGF receptor (VEGFR) inhibitors, were developed as eye\u2010drops, their efficacies were insufficient in clinical. In this study, we evaluated ocular pharmacokinetics and pharmacological activities of regorafenib and pazopanib after ocular instillation in multiple animal species. In rats, both regorafenib and pazopanib showed high enough concentrations in the posterior eye tissues to inhibit VEGFR. In laser\u2010induced rat CNV model, regorafenib showed clear reduction in CNV area. On the other hand, the concentrations of regorafenib and pazopanib in the posterior eye tissues were much lower after ocular instillation in rabbits and monkeys compared to those in rats. Pazopanib did not show any improvement in monkey model. Regorafenib was nano\u2010crystalized to improve its drug delivery to the posterior eye tissues. The nano\u2010crystalized formulation of regorafenib showed higher concentrations in the posterior segments in rabbits compared to its microcrystal suspension. From these studies, large interspecies differences were found in ocular delivery to the posterior segments after ocular instillation. Such large interspecies difference could be the reason for the insufficient efficacies of regorafenib and pazopanib in clinical studies. Nano\u2010crystallization was suggested to be one of the effective ways to overcome this issue.<\/jats:p>","DOI":"10.1002\/prp2.545","type":"journal-article","created":{"date-parts":[[2019,11,20]],"date-time":"2019-11-20T03:24:55Z","timestamp":1574220295000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":30,"title":["Species differences in ocular pharmacokinetics and pharmacological activities of regorafenib and pazopanib eye\u2010drops among rats, rabbits and monkeys"],"prefix":"10.1002","volume":"7","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5282-3736","authenticated-orcid":false,"given":"Shinya","family":"Horita","sequence":"first","affiliation":[{"name":"R&amp;D Division Kyowa Kirin Co., Ltd. Sunto\u2010gun Shizuoka Japan"},{"name":"Department of Clinical Pharmaceutics School of Pharmaceutical Sciences University of Shizuoka Sunto\u2010gun Shizuoka Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miwa","family":"Watanabe","sequence":"additional","affiliation":[{"name":"R&amp;D Division Kyowa Kirin Co., Ltd. Sunto\u2010gun Shizuoka Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mai","family":"Katagiri","sequence":"additional","affiliation":[{"name":"R&amp;D Division Kyowa Kirin Co., Ltd. Sunto\u2010gun Shizuoka Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroaki","family":"Nakamura","sequence":"additional","affiliation":[{"name":"R&amp;D Division Kyowa Kirin Co., Ltd. Sunto\u2010gun Shizuoka Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroki","family":"Haniuda","sequence":"additional","affiliation":[{"name":"Production Division Kyowa Kirin Co., Ltd. Sunto\u2010gun Shizuoka Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomoyuki","family":"Nakazato","sequence":"additional","affiliation":[{"name":"Production Division Kyowa Kirin Co., Ltd. Sunto\u2010gun Shizuoka Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshiyuki","family":"Kagawa","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmaceutics School of Pharmaceutical Sciences University of Shizuoka Sunto\u2010gun Shizuoka Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2019,11,20]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1001\/archopht.122.4.564"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1076\/opep.11.2.67.28158"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(12)60282-7"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1159\/000438969"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ophtha.2009.10.007"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1080\/14728214.2017.1362390"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0002-9440(10)64525-7"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(07)61104-0"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa042760"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa062655"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-0420.2006.00736.x"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1102673"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ophtha.2012.03.053"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ophtha.2012.09.006"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ophtha.2016.10.036"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1517\/14728214.2014.884559"},{"key":"e_1_2_9_18_1","unstructured":"Food and Drug Administration labeling information (Regorafenib) https:\/\/www.accessdata.fda.gov\/drugsatfda_docs\/label\/2018\/203085s008lbl.pdf."},{"key":"e_1_2_9_19_1","unstructured":"Food and Drug Administration labeling information (Pazopanib) https:\/\/www.accessdata.fda.gov\/drugsatfda_docs\/label\/2017\/022465s024s025lbl.pdf."},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ophtha.2014.09.036"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1097\/ICU.0000000000000147"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.1111\/bcp.13502"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejphar.2011.05.016"},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jconrel.2010.10.007"},{"key":"e_1_2_9_25_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijpharm.2007.03.011"},{"key":"e_1_2_9_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.drudis.2017.01.003"},{"key":"e_1_2_9_27_1","first-page":"399","article-title":"Nanocrystal for ocular drug delivery: hope or hype","volume":"6","author":"Sharma OP","year":"2016","journal-title":"Drug Deliv Transl Res"},{"key":"e_1_2_9_28_1","doi-asserted-by":"publisher","DOI":"10.1001\/archopht.126.7.946"},{"key":"e_1_2_9_29_1","doi-asserted-by":"publisher","DOI":"10.1001\/archopht.120.3.338"},{"key":"e_1_2_9_30_1","doi-asserted-by":"publisher","DOI":"10.1167\/iovs.09-4890"},{"key":"e_1_2_9_31_1","doi-asserted-by":"publisher","DOI":"10.1001\/archophthalmol.2011.210"},{"key":"e_1_2_9_32_1","doi-asserted-by":"publisher","DOI":"10.1002\/jps.2600630304"},{"key":"e_1_2_9_33_1","doi-asserted-by":"publisher","DOI":"10.1002\/jps.2600651230"},{"key":"e_1_2_9_34_1","doi-asserted-by":"publisher","DOI":"10.1208\/s12248-010-9183-3"},{"key":"e_1_2_9_35_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-0420.2007.00885.x"},{"key":"e_1_2_9_36_1","doi-asserted-by":"publisher","DOI":"10.1167\/iovs.12-10169"},{"key":"e_1_2_9_37_1","unstructured":"Food and Drug Administration pharmacology review information (Regorafenib) https:\/\/www.accessdata.fda.gov\/drugsatfda_docs\/nda\/2012\/203085Orig1s000PharmR.pdf."},{"key":"e_1_2_9_38_1","unstructured":"Food and Drug Administration pharmacology review information (Pazopanib) https:\/\/www.accessdata.fda.gov\/drugsatfda_docs\/nda\/2009\/022465s000_PharmR.pdf."},{"key":"e_1_2_9_39_1","doi-asserted-by":"publisher","DOI":"10.1167\/iovs.12-10473"},{"key":"e_1_2_9_40_1","first-page":"3","article-title":"Scientific viewpoints in ocular toxicity assessment: departure from conventional practice","volume":"32","author":"Onodera H","year":"2013","journal-title":"Anim. Eye Res"}],"container-title":["Pharmacology Research &amp; Perspectives"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/prp2.545","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/prp2.545","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/bpspubs.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/prp2.545","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,8,22]],"date-time":"2023-08-22T00:24:13Z","timestamp":1692663853000},"score":1,"resource":{"primary":{"URL":"https:\/\/bpspubs.onlinelibrary.wiley.com\/doi\/10.1002\/prp2.545"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,11,20]]},"references-count":39,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2019,12]]}},"alternative-id":["10.1002\/prp2.545"],"URL":"https:\/\/doi.org\/10.1002\/prp2.545","archive":["Portico"],"relation":{},"ISSN":["2052-1707","2052-1707"],"issn-type":[{"value":"2052-1707","type":"print"},{"value":"2052-1707","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,11,20]]},"assertion":[{"value":"2019-10-10","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2019-10-23","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2019-11-20","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e00545"}}