{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T06:47:16Z","timestamp":1792133236842,"version":"4.4.0"},"reference-count":36,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T00:00:00Z","timestamp":1790035200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T00:00:00Z","timestamp":1790035200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100004325","name":"AstraZeneca","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100004325","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bpspubs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Pharmacology Res &amp;amp; Perspec"],"published-print":{"date-parts":[[2026,10]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Savolitinib is an oral, potent, selective CNS\u2010penetrant MET\u2010tyrosine kinase inhibitor that in\u00a0vitro studies indicate is metabolized by cytochrome P450 (CYP) enzymes, including CYP1A2, and by non\u2010CYP enzymes, such as aldehyde oxidase (AO). Savolitinib primary metabolites, M2 and M3, are formed mainly by CYP1A2 and AO, respectively. This Phase 1, open\u2010label study evaluated the impact of CYP1A2 inhibition by fluvoxamine on the pharmacokinetics of savolitinib and its metabolites in 16 healthy male volunteers. Volunteers received a single oral dose of 300\u2009mg savolitinib and, following a\u2009\u2265\u200910\u2010day washout period, 50\u2009mg twice\u2010daily oral fluvoxamine for 6\u2009days, with a single oral dose of 300\u2009mg savolitinib co\u2010administered on Day 5. Serial pharmacokinetic samples were collected during both study periods. Savolitinib, M2, and M3 were measured using high\u2010performance liquid chromatography with tandem mass spectrometry. Systemic exposure of savolitinib increased by approximately 2\u2010fold (maximum plasma concentration) and 3\u2010fold (area under the plasma concentration\u2010time curve from time 0 to infinity) when savolitinib was administered with fluvoxamine compared with savolitinib alone. Systemic exposure of M2 and M3 decreased and increased, respectively, when savolitinib was administered with vs. without fluvoxamine, while the ratio of M2\/savolitinib was reduced and that of M3\/savolitinib remained unchanged. These data suggest a significant drug\u2013drug interaction between savolitinib and the strong CYP1A2 inhibitor, fluvoxamine, and that CYP1A2 is involved in the formation of M2, but not M3. No new safety concerns were observed when savolitinib was administered alone or with twice\u2010daily fluvoxamine.<\/jats:p>","DOI":"10.1002\/prp2.70321","type":"journal-article","created":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T05:37:49Z","timestamp":1790141869000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Evaluating the Impact of\n                    <scp>CYP1A2<\/scp>\n                    Inhibition on the Pharmacokinetics of Savolitinib: A Phase 1 Open\u2010Label Study"],"prefix":"10.1002","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-4319-6728","authenticated-orcid":false,"given":"Kowser","family":"Miah","sequence":"first","affiliation":[{"name":"Clinical Pharmacology and Quantitative Pharmacology, CPSS AstraZeneca  Waltham Massachusetts 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Product information for human medicinal products \u201dhttps:\/\/swissmedicinfo\u2010pro.ch\/showText.aspx?textType=FI&lang=EN&authNr=70151&supportMultipleResults=1."},{"key":"e_1_2_11_36_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.clpt.2004.12.191"},{"key":"e_1_2_11_37_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcph.1145"}],"container-title":["Pharmacology Research &amp; Perspectives"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/bpspubs.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/prp2.70321","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/bpspubs.onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/prp2.70321","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/bpspubs.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/prp2.70321","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T06:14:50Z","timestamp":1792131290000},"score":1,"resource":{"primary":{"URL":"https:\/\/bpspubs.onlinelibrary.wiley.com\/doi\/10.1002\/prp2.70321"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,22]]},"references-count":36,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2026,10]]}},"alternative-id":["10.1002\/prp2.70321"],"URL":"https:\/\/doi.org\/10.1002\/prp2.70321","archive":["Portico"],"relation":{},"ISSN":["2052-1707","2052-1707"],"issn-type":[{"value":"2052-1707","type":"print"},{"value":"2052-1707","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,22]]},"assertion":[{"value":"2026-04-24","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-08-19","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-09-22","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70321"}}