{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,26]],"date-time":"2026-10-26T05:39:05Z","timestamp":1792993145213,"version":"4.5.0"},"reference-count":35,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T00:00:00Z","timestamp":1791763200000},"content-version":"vor","delay-in-days":11,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"},{"start":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T00:00:00Z","timestamp":1790812800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["accp1.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Clinical Pharma"],"published-print":{"date-parts":[[2026,10]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Methotrexate is a key chemotherapeutic agent for treating pediatric acute lymphoblastic leukemia (ALL); however, its pharmacokinetics exhibit substantial inter\u2010individual variability. Population pharmacokinetic (PPK) models have identified body weight and renal function as major determinants of methotrexate clearance. Nonetheless, the optimal PPK model for Japanese pediatric patients, considering hydration status, has not yet been established. This study aimed to develop a PPK model of high\u2010dose methotrexate specifically for Japanese pediatric patients with ALL. A retrospective PPK analysis was performed in pediatric patients with ALL, who were treated with high\u2010dose methotrexate at the Tokyo Medical and Dental University Hospital. Data from 38 patients (504 methotrexate concentrations; 27 for model development and 11 for validation) were analyzed using a two\u2010compartment model in NONMEM. Predictive performances of the newly developed and previously published models were assessed using the validation dataset. In the final model, clearance was described as a function of body surface area and hydration volume rate per body surface area (HYDR), whereas intercompartmental clearance was associated with age and HYDR. Evaluation using the validation dataset showed that the developed model had the best predictive performance among the evaluated models (median prediction error, 1.79%; median absolute prediction error, 13.3%; percentage of predictions with an absolute prediction error \u226420%, 70.3%; percentage of predictions with an absolute prediction error \u226430%, 82.9%). Simulation revealed modestly improved target\u2010attainment rates at relatively high hydration rates. These findings highlight the importance of fluid management and support the incorporation of hydration parameters into individualized high\u2010dose methotrexate therapy.<\/jats:p>","DOI":"10.1002\/jcph.70310","type":"journal-article","created":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T11:47:04Z","timestamp":1791805624000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Development and Evaluation of a Population Pharmacokinetic Model for High\u2010Dose Methotrexate in Japanese Pediatric Patients with Acute Lymphoblastic Leukemia"],"prefix":"10.1002","volume":"66","author":[{"given":"Takuya","family":"Suzuoka","sequence":"first","affiliation":[{"name":"Department of Pharmacy Institute of Science Tokyo Hospital  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tsubura","family":"Noda","sequence":"additional","affiliation":[{"name":"Department of Pharmacy Institute of Science Tokyo Hospital  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kota","family":"Tsuge","sequence":"additional","affiliation":[{"name":"Department of Pharmacy Institute of Science Tokyo Hospital  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasuyoshi","family":"Ishiwata","sequence":"additional","affiliation":[{"name":"Department of Pharmacy Institute of Science Tokyo Hospital  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3898-2068","authenticated-orcid":false,"given":"Toshinori","family":"Hirai","sequence":"additional","affiliation":[{"name":"Department of Pharmacy Institute of Science Tokyo Hospital  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3349-3705","authenticated-orcid":false,"given":"Takeshi","family":"Isoda","sequence":"additional","affiliation":[{"name":"Department of Pediatrics and Developmental Biology, Graduate School of Medical and Dental Sciences Institute of Science Tokyo  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7580-9184","authenticated-orcid":false,"given":"Masatoshi","family":"Takagi","sequence":"additional","affiliation":[{"name":"Department of Pediatrics and Developmental Biology, Graduate School of Medical and Dental Sciences Institute of Science Tokyo  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3169-7210","authenticated-orcid":false,"given":"Masashi","family":"Nagata","sequence":"additional","affiliation":[{"name":"Department of Pharmacy Institute of Science Tokyo Hospital  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,10,12]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI112872"},{"key":"e_1_2_9_3_1","unstructured":"KatsuyoshiK.A multicenter phase III study in children adolescent and young adult and adults with newly diagnosed B\u2010cell precursor acute lymphoblastic leukemia (JPLSG\u2010ALL\u2010B19) Japan Registry of Clinical Trials. Published July 13 2021 Modified November 21 2024 Accessed April 9 2025.https:\/\/jrct.mhlw.go.jp\/en\u2010latest\u2010detail\/jRCTs041210040"},{"issue":"10","key":"e_1_2_9_4_1","first-page":"3294","article-title":"Improved treatment results in childhood B\u2010cell neoplasms with tailored intensification of therapy: a report of the Berlin\u2010Frankfurt\u2010Munster Group Trial NHL\u2010BFM 90","volume":"94","author":"Reiter 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methotrexate in pediatric acute lymphoblastic leukemia: predictors of delayed clearance and the effect of increased hydration rate on methotrexate clearance","volume":"12","author":"Chen AR","year":"2020","journal-title":"Cureus"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.2147\/CMAR.S172117"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2023.1280587"},{"issue":"4","key":"e_1_2_9_20_1","first-page":"489","article-title":"Performance evaluation of \u201cNanopia\u00ae eTDM Methotrexate\u201d for the quantitative determination of methotrexate in human serum using an automated clinical chemistry analyzer","volume":"64","author":"Tanaka Y","year":"2015","journal-title":"Jpn J Med 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