{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,6]],"date-time":"2026-09-06T17:32:58Z","timestamp":1788715978763,"version":"build-2803163510"},"reference-count":29,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2020,1,8]],"date-time":"2020-01-08T00:00:00Z","timestamp":1578441600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100012524","name":"American Lebanese Syrian Associated Charities","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100012524","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","award":["R01CA154619"],"award-info":[{"award-number":["R01CA154619"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Brit J Clinical Pharma"],"published-print":{"date-parts":[[2020,2]]},"abstract":"<jats:sec><jats:title>Aims<\/jats:title><jats:p>No population pharmacokinetic studies of high\u2010dose methotrexate (HDMTX) have been conducted in infants with brain tumours, which are a vulnerable population. The aim of this study was to evaluate HDMTX disposition in these children to provide a rational basis for MTX dosing.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Patients received 4 monthly courses of HDMTX (5 g\/m<jats:sup>2<\/jats:sup> or 2.5 g\/m<jats:sup>2<\/jats:sup> for infants aged \u226431 days) as a 24\u2010h infusion. Serial samples were analysed for MTX by an enzyme immunoassay method. Pharmacokinetic parameters were estimated using nonlinear mixed effects population modelling. Demographics, concomitant medications and genetic polymorphisms were considered as pharmacokinetic covariates while MTX exposure and patient age were considered as covariates for Grade 3 and 4 toxicities.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The population pharmacokinetics of HDMTX were estimated in 178 patients (age range 0.02\u20134.7 years) in 648 courses. The population clearance and volume were 90 mL\/min\/m<jats:sup>2<\/jats:sup> and 14.4 L\/m<jats:sup>2<\/jats:sup>, respectively. Significant covariates on body surface area adjusted MTX clearance included estimated glomerular filtration rate and co\u2010treatment with dexamethasone or vancomycin. No significant association was observed between MTX toxicity and MTX exposure, patient age, leucovorin dosage or duration. MTX clearance in infants \u226431 days at enrolment was 44% lower than in older infants, but their incidence of toxicity was not higher since they also received a lower MTX dosage.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>By aggressively following institutional clinical guidelines, HDMTX\u2010related toxicities were low, and using covariates from the population pharmacokinetic model enabled the calculation of a rational dosage for this patient population for future clinical trials.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bcp.14160","type":"journal-article","created":{"date-parts":[[2019,10,28]],"date-time":"2019-10-28T13:58:08Z","timestamp":1572271088000},"page":"362-371","source":"Crossref","is-referenced-by-count":28,"title":["Pharmacokinetic basis for dosing high\u2010dose methotrexate in infants and young children with malignant brain tumours"],"prefix":"10.1111","volume":"86","author":[{"given":"John C.","family":"Panetta","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Sciences St. Jude Children's Research Hospital  Memphis TN USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessica K.","family":"Roberts","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences St. Jude Children's Research Hospital  Memphis TN USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Biostatistics St. Jude Children's Research Hospital  Memphis TN USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tong","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Biostatistics St. Jude Children's Research Hospital  Memphis TN USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vinay M.","family":"Daryani","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences St. Jude Children's Research Hospital  Memphis TN USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"K. 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