{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,8]],"date-time":"2026-03-08T18:22:29Z","timestamp":1772994149317,"version":"3.50.1"},"reference-count":35,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2025,9,6]],"date-time":"2025-09-06T00:00:00Z","timestamp":1757116800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2025,9,6]],"date-time":"2025-09-06T00:00:00Z","timestamp":1757116800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100002336","name":"Daiichi Sankyo Company","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100002336","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["accp1.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Clinical Pharma"],"published-print":{"date-parts":[[2025,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Valemetostat is a dual inhibitor of EZH2\/1 approved in Japan for the treatment of relapsed\/refractory (R\/R) adult T\u2013cell lymphoma\/leukemia (ATLL) and R\/R peripheral T\u2013cell lymphoma (PTCL). It is administered orally once daily (QD) at 200 mg. Here, we present comprehensive population pharmacokinetic (PPK) and exposure\u2013response (ER) analyses of valemetostat. The PPK model included data from six clinical trials in patients with non\u2013Hodgkin lymphoma, including ATLL\/PTCL, or healthy participants. ER efficacy analyses were based on data from one phase 2 clinical trial in patients with PTCL; ER safety analyses used data from three trials in patients with ATLL or PTCL. Valemetostat unbound average concentration up to event was used as the exposure metric. ER analyses included overall response rates for efficacy and six safety endpoints (any Grade \u22653 treatment\u2013emergent adverse event [TEAE]; Grade \u22653 thrombocytopenia, anemia, and neutropenia; and dose reduction and interruption due to TEAEs). Valemetostat pharmacokinetics were well described by a three\u2013compartment model, with a sequential linked zero\u2013\/first\u2013order absorption, a saturable binding component in the central compartment, and linear elimination of unbound valemetostat from the central compartment. Alpha\u20101\u2010acid glycoprotein was the only identified covariate significantly affecting total valemetostat exposure but had no impact on unbound exposure. The ER relationship on efficacy was not significant, and positive relationships were identified for multiple safety endpoints. Safety simulations across different doses suggested an acceptable safety profile for 200 mg QD. Overall, these analyses support the favorable benefit\u2013risk profile of valemetostat at 200 mg QD in patients with R\/R PTCL.<\/jats:p>","DOI":"10.1002\/jcph.70100","type":"journal-article","created":{"date-parts":[[2025,9,6]],"date-time":"2025-09-06T09:14:53Z","timestamp":1757150093000},"page":"1699-1711","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Population Pharmacokinetics of Valemetostat and Exposure\u2013Response Analyses of Efficacy and Safety in Patients with Relapsed\/Refractory Peripheral T\u2013Cell Lymphoma"],"prefix":"10.1002","volume":"65","author":[{"given":"Hiroyuki","family":"Inoue","sequence":"first","affiliation":[{"name":"Daiichi Sankyo Co., Ltd  Tokyo Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaoning","family":"Wang","sequence":"additional","affiliation":[{"name":"Metrum Research Group  Tariffville CT USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ramon","family":"Garcia","sequence":"additional","affiliation":[{"name":"Metrum Research Group  Tariffville CT USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Brian","family":"Reilly","sequence":"additional","affiliation":[{"name":"Metrum Research Group  Tariffville CT USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"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":[{"role":"author","vocabulary":"crossref"}]},{"given":"YoungJun","family":"Yoo","sequence":"additional","affiliation":[{"name":"Daiichi Sankyo Co., Ltd  Tokyo Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yvonne","family":"Lau","sequence":"additional","affiliation":[{"name":"Daiichi Sankyo Inc.  Basking Ridge NJ USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yang","family":"Chen","sequence":"additional","affiliation":[{"name":"Daiichi Sankyo Inc.  Basking Ridge NJ USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2025,9,6]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2018.08.058"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.6198"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40265-022-01800-5"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.exphem.2015.05.001"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1111\/cas.13655"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2019.10.083"},{"key":"e_1_2_11_8_1","unstructured":"Daiichi Sankyo Co. Ltd. Press release.EZHARMIA\u00ae Approved in Japan as First Dual EZH1 and EZH2 Inhibitor Therapy for Patients with Peripheral T\u2010Cell Lymphoma.2024. Accessed March 2025.https:\/\/www.daiichisankyo.com\/files\/news\/pressrelease\/pdf\/202406\/20240624_E2.pdf"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood.2022016862"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(24)00503-5"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2024.42.16_suppl.TPS4180"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-23-3383"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1002\/psp4.13201"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.1002\/psp4.13203"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(24)00502-3"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2023-179304"},{"key":"e_1_2_11_17_1","doi-asserted-by":"publisher","DOI":"10.1111\/cts.70279"},{"key":"e_1_2_11_18_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpdd.1315"},{"key":"e_1_2_11_19_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpdd.1544"},{"key":"e_1_2_11_20_1","doi-asserted-by":"publisher","DOI":"10.1214\/08-AOAS191"},{"key":"e_1_2_11_21_1","doi-asserted-by":"publisher","DOI":"10.18637\/jss.v080.i01"},{"key":"e_1_2_11_22_1","doi-asserted-by":"publisher","DOI":"10.1201\/9780429029608"},{"key":"e_1_2_11_23_1","doi-asserted-by":"publisher","DOI":"10.1214\/17-EJS1337SI"},{"key":"e_1_2_11_24_1","volume-title":"Bayesian data analysis","author":"Gelman A","year":"2004"},{"key":"e_1_2_11_25_1","doi-asserted-by":"publisher","DOI":"10.18637\/jss.v076.i01"},{"key":"e_1_2_11_26_1","unstructured":"The R Foundation for Statistical Computation.R: regulatory compliance and validation issues: a guidance document for the use of R in regulated clinical trial environments.Institute for Statistics and Mathematics;2021. 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