{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,11]],"date-time":"2026-04-11T06:08:10Z","timestamp":1775887690858,"version":"3.50.1"},"reference-count":31,"publisher":"Wiley","issue":"11","license":[{"start":{"date-parts":[[2025,10,28]],"date-time":"2025-10-28T00:00:00Z","timestamp":1761609600000},"content-version":"vor","delay-in-days":0,"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":[[2025,11]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Valemetostat tosylate (valemetostat) is an oral, potent, dual inhibitor of enhancer of zeste homolog (EZH)2\/1, under investigation in non\u2010Hodgkin lymphomas (NHLs) and solid tumors. In\u00a0vitro, it inhibits cytochrome P450 3A (CYP3A) and P\u2010glycoprotein (P\u2010gp) when combined with sensitive CYP3A or P\u2010gp substrates. This drug\u2013drug interaction (DDI) sub\u2010study is part of the phase 1 trial of valemetostat monotherapy (DS3201\u2010A\u2010J101; NCT02732275), assessing the effect of valemetostat on the pharmacokinetics (PK) of sensitive CYP3A and P\u2010gp substrates midazolam and digoxin, respectively, in patients with relapsed or refractory NHL, and its safety and efficacy. Patients received two simultaneous single doses of midazolam and digoxin: once alone and once concomitantly with a daily 200\u2009mg valemetostat dose in a 28\u2010day\u2009cycle. Of 24 enrolled patients, 15 and 16 were evaluable for PK analyses of midazolam and digoxin, respectively. Valemetostat co\u2010administration caused a slight decrease in midazolam maximum plasma concentration (\n                    <jats:italic>C<\/jats:italic>\n                    <jats:sub>max<\/jats:sub>\n                    ) (geometric least\u2010squares mean ratio [GMR], 0.966 [90% confidence interval (CI), 0.769\u20131.21]) and area under the plasma concentration\u2013time curve up to the last quantifiable time (AUC\n                    <jats:sub>last<\/jats:sub>\n                    ) (GMR, 0.87 [90% CI, 0.75\u20131.03]), increased digoxin\n                    <jats:italic>C<\/jats:italic>\n                    <jats:sub>max<\/jats:sub>\n                    (GMR, 1.30 [90% CI, 1.07\u20131.57]), and AUC\n                    <jats:sub>last<\/jats:sub>\n                    (GMR, 1.27 [90% CI, 1.06\u20131.52]). The overall safety and efficacy outcomes were similar to other studies. Valemetostat showed a manageable and tolerable safety profile, without clinically meaningful DDI with sensitive CYP3A substrates. Co\u2010administration of valemetostat and P\u2010gp substrates with a narrow therapeutic index may require careful monitoring and\/or DDI risk management.\n                  <\/jats:p>","DOI":"10.1111\/cts.70330","type":"journal-article","created":{"date-parts":[[2025,10,29]],"date-time":"2025-10-29T00:47:53Z","timestamp":1761698873000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Effect of Valemetostat on the Pharmacokinetics of Midazolam and Digoxin: A Phase 1 Drug\u2013Drug Interaction Study in Patients With Non\u2010Hodgkin Lymphoma"],"prefix":"10.1111","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-5608-5254","authenticated-orcid":false,"given":"Masaya","family":"Tachibana","sequence":"first","affiliation":[{"name":"Daiichi Sankyo Co., Ltd.  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