{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,31]],"date-time":"2026-01-31T02:12:00Z","timestamp":1769825520301,"version":"3.49.0"},"reference-count":34,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2024,7,30]],"date-time":"2024-07-30T00:00:00Z","timestamp":1722297600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002973","name":"Daiichi-Sankyo","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100002973","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["CPT Pharmacom &amp; Syst Pharma"],"published-print":{"date-parts":[[2024,10]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Valemetostat is an EZH2\/1 inhibitor that has been approved in Japan for the treatment of patients with relapsed\/refractory adult T\u2010cell leukemia\/lymphoma, based mainly on results from a single\u2010arm phase II trial. It is currently under investigation worldwide for the treatment of other non\u2010Hodgkin lymphomas (NHLs), including peripheral T\u2010cell lymphoma, and for solid tumors. Semi\u2010mechanistic population pharmacokinetic modeling of total and unbound valemetostat and an analysis of the platelet time course during treatment with valemetostat were conducted using data from five clinical trials (two in patients with NHL and three in healthy volunteers). Pharmacokinetic data, including 3162 total\/1871 unbound valemetostat observations from 102 patients and 72 healthy volunteers, were described by a three\u2010compartment model with sequential zero\u2010\/first\u2010order absorption and saturable binding in the central compartment. Alpha\u20101\u2010acid glycoprotein (AAG) was the most influential covariate for total valemetostat exposure, yet had little impact on unbound exposure, meaning no dose adjustment was warranted based on AAG levels. The longitudinal platelet data from 101 patients (2313 observations) were adequately described by a modified Friberg model with two proliferation compartments, which characterized unique spontaneous recovery of platelet counts without dose modifications. A model\u2010based simulation quantitatively assessed the proposed dose\u2010adjustment guidance in case of platelet count decreased by comparing the probability of treatment discontinuation due to platelet count decreased with or without the dose adjustment. In summary, the models described observed total and unbound valemetostat concentrations and a unique time course of platelets during treatment, which can justify the clinical dose and provide dose\u2010adjustment guidance.<\/jats:p>","DOI":"10.1002\/psp4.13201","type":"journal-article","created":{"date-parts":[[2024,7,30]],"date-time":"2024-07-30T10:40:01Z","timestamp":1722336001000},"page":"1641-1654","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Population pharmacokinetics of total and unbound valemetostat and platelet dynamics in healthy volunteers and patients with non\u2010Hodgkin lymphoma"],"prefix":"10.1002","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0206-2956","authenticated-orcid":false,"given":"Masato","family":"Fukae","sequence":"first","affiliation":[{"name":"Daiichi Sankyo Co., Ltd.  Tokyo Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kyle","family":"Baron","sequence":"additional","affiliation":[{"name":"Metrum Research Group  Tariffville Connecticut USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Masaya","family":"Tachibana","sequence":"additional","affiliation":[{"name":"Daiichi Sankyo Co., Ltd.  Tokyo Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"John","family":"Mondick","sequence":"additional","affiliation":[{"name":"Metrum Research Group  Tariffville Connecticut USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Takako","family":"Shimizu","sequence":"additional","affiliation":[{"name":"Daiichi Sankyo Co., Ltd.  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Poster Presented at: European Hematology Association September 6 2021; Virtual."},{"key":"e_1_2_10_14_1","first-page":"4070","article-title":"First\u2010in\u2010human study of the EZH1\/2 dual inhibitor DS\u20103201b in patients with relapsed or refractory non\u2010Hodgkin lymphomas \u2013 preliminary results","volume":"130","author":"Maruyama D","year":"2017","journal-title":"Blood"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpdd.1315"},{"key":"e_1_2_10_16_1","first-page":"226","article-title":"Effect of alpha\u20101\u2010acid glycoprotein binding on pharmacokinetics and pharmacodynamics","volume":"14","author":"Huang Z","year":"2013","journal-title":"Curr Drug Metab"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1080\/21655979.2022.2036303"},{"key":"e_1_2_10_18_1","unstructured":"KurataA MatsukiS FukaeM ShinoharaS TachibanaM ShimizuT.A DDI study to evaluate the effect of multiple oral administration of rifampicin on the pharmacokinetics of valemetostat in healthy participants. 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