{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,29]],"date-time":"2026-06-29T16:08:52Z","timestamp":1782749332222,"version":"3.54.5"},"reference-count":26,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2025,10,13]],"date-time":"2025-10-13T00:00:00Z","timestamp":1760313600000},"content-version":"vor","delay-in-days":12,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clinical Translational Sci"],"published-print":{"date-parts":[[2025,10]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Valemetostat tosylate (valemetostat) is an oral, potent, selective dual inhibitor of enhancer of zeste homolog (EZH)2 and EZH1, approved in Japan for the treatment of relapsed\/refractory adult T\u2010cell leukemia\/lymphoma and peripheral T\u2010cell lymphoma. Results from in\u00a0vitro and clinical studies suggest that valemetostat is pre\u2010systemically metabolized by cytochrome P450 3A (CYP3A) in the gut and excreted into bile and urine via P\u2010glycoprotein (P\u2010gp) in its unchanged form and as an oxidative metabolite. In this study, a physiologically based pharmacokinetic (PBPK) model was developed by utilizing available in\u00a0vitro and clinical pharmacokinetics (PK) data to predict the impact of CYP3A and P\u2010gp modulators on the PK of valemetostat. The developed PBPK model was validated against clinical drug\u2013drug interaction studies with a moderate CYP3A inhibitor (fluconazole), a strong CYP3A\/P\u2010gp dual inhibitor (itraconazole), and a strong CYP3A\/P\u2010gp dual inducer (rifampicin), indicating that the contributions of CYP3A and P\u2010gp in the gut and liver to valemetostat PK were appropriately described in the PBPK model. The validated model was applied to assess the effect of either a CYP3A or a P\u2010gp inhibitor, or a moderate CYP3A inducer on valemetostat PK. The PBPK model incorporating the contribution of CYP3A and P\u2010gp in the gut and liver effectively estimated the effect of CYP3A\/P\u2010gp modulators on valemetostat PK and can be used to inform dose recommendations for valemetostat upon coadministration with other treatments.<\/jats:p>","DOI":"10.1111\/cts.70333","type":"journal-article","created":{"date-parts":[[2025,10,14]],"date-time":"2025-10-14T01:17:11Z","timestamp":1760404631000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Physiologically Based Pharmacokinetic Modeling of Valemetostat to Inform Dose Recommendations When Coadministered With\n                    <scp>CYP3A<\/scp>\n                    \/P\u2010gp Modulators"],"prefix":"10.1111","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7496-5911","authenticated-orcid":false,"given":"Akiko","family":"Watanabe","sequence":"first","affiliation":[{"name":"Daiichi Sankyo Co., Ltd.  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Noriko","family":"Okudaira","sequence":"additional","affiliation":[{"name":"Certara UK, Ltd.  Sheffield UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-5608-5254","authenticated-orcid":false,"given":"Masaya","family":"Tachibana","sequence":"additional","affiliation":[{"name":"Daiichi Sankyo Co., Ltd.  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miho","family":"Kazui","sequence":"additional","affiliation":[{"name":"Daiichi Sankyo Co., Ltd.  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masakatsu","family":"Kotsuma","sequence":"additional","affiliation":[{"name":"Daiichi Sankyo Co., Ltd.  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takako","family":"Shimizu","sequence":"additional","affiliation":[{"name":"Daiichi Sankyo Co., Ltd.  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yvonne","family":"Lau","sequence":"additional","affiliation":[{"name":"Daiichi Sankyo, Inc.  Basking Ridge New Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,10,13]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1111\/cas.13326"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood.2022016862"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(24)00503-5"},{"key":"e_1_2_9_5_1","volume-title":"The Japanese Society of Medical Oncology (JSMO) Annual Meeting","author":"Naito Y.","year":"2025"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(24)00502-3"},{"key":"e_1_2_9_7_1","unstructured":"Daiichi Sankyo \u201cEZHARMIA Approved in Japan as First Dual EZH1 and EZH2 Inhibitor Therapy for Patients With Peripheral T\u2010Cell Lymphoma \u201dhttps:\/\/www.daiichisankyo.com\/files\/news\/pressrelease\/pdf\/202406\/20240624_E2.pdf."},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1002\/psp4.13203"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpdd.1315"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1002\/psp4.13201"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1111\/cts.13613"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1111\/cts.70279"},{"key":"e_1_2_9_13_1","unstructured":"E. 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