{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,20]],"date-time":"2026-09-20T14:39:02Z","timestamp":1789915142412,"version":"4.0.1"},"reference-count":44,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2018,5,23]],"date-time":"2018-05-23T00:00:00Z","timestamp":1527033600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100002915","name":"Fondation pour la Recherche M\u00e9dicale","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100002915","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100006364","name":"Institut National Du Cancer","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100006364","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":[[2018,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Growing evidence suggests that polymorphisms of genes coding for transporters or enzymes may partially explain the large between subject variability reported for methotrexate (MTX) pharmacokinetics (PK). This prospective study aimed to develop a population PK\u2010pharmacogenetic model to evaluate the part of between\u2010subject variability due to single\u2010nucleotide polymorphisms (SNPs) in transporters and enzyme genes implicated in MTX distribution and elimination. MTX concentrations and 54 SNPs (located in<jats:italic>ABCB1<\/jats:italic>,<jats:italic>ABCC1<\/jats:italic>,<jats:italic>ABCC2<\/jats:italic>,<jats:italic>ABCC3<\/jats:italic>,<jats:italic>ABCC4<\/jats:italic>,<jats:italic>ABCG2<\/jats:italic>,<jats:italic>SLC19A1<\/jats:italic>,<jats:italic>SLCO1B1<\/jats:italic>, and<jats:italic>UGT1A1<\/jats:italic>genes) were analyzed in patients treated with MTX included in the OS2006\/sarcoma\u201009 trial (a multicenter, open\u2010label, phase III trial, ClinicalTrials.gov. Identifier: NCT00470223). PK data were analyzed using the nonlinear mixed\u2010effect modeling software program Monolix. The influence of each SNP was evaluated using a stepwise procedure under additive, recessive, or dominant genetic model. The likelihood ratio test was used to test the effect of each SNP on PK parameters. Overall, 187 patients with 7898 MTX blood concentrations were included in the PK\u2010pharmacogenetic analysis. A 2\u2010compartment model adequately described the data. Although high\u2010dose MTX dosing recommendations in pediatric patients are currently based on body surface area, body weight was more predictive of clearance between\u2010subject variability than body surface area. The most significant polymorphism associated with MTX clearance was rs13120400 (on the<jats:italic>ABCG2<\/jats:italic>gene) under the recessive genetic model (<jats:italic>P<\/jats:italic>&lt; .0001). GG genotype carriers for rs13120400 appeared to have a moderate decrease in MTX exposure compared to AA or GA carriers.<\/jats:p>","DOI":"10.1002\/jcph.1252","type":"journal-article","created":{"date-parts":[[2018,5,23]],"date-time":"2018-05-23T14:11:27Z","timestamp":1527084687000},"page":"1541-1549","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":40,"title":["A Pharmacokinetic and Pharmacogenetic Analysis of Osteosarcoma Patients Treated With High\u2010Dose Methotrexate: Data From the OS2006\/Sarcoma\u201009 Trial"],"prefix":"10.1002","volume":"58","author":[{"given":"Gabrielle","family":"Lui","sequence":"first","affiliation":[{"name":"EA 7323 Universit\u00e9 Paris Descartes Sorbonne Paris Cit\u00e9 Paris France"},{"name":"Clinical Pharmacology Department Cochin Hospital Paris France"},{"name":"CIC\u20101419 Inserm Cochin\u2010Necker Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean\u2010Marc","family":"Treluyer","sequence":"additional","affiliation":[{"name":"EA 7323 Universit\u00e9 Paris Descartes Sorbonne Paris Cit\u00e9 Paris France"},{"name":"Clinical Pharmacology Department Cochin Hospital Paris France"},{"name":"CIC\u20101419 Inserm Cochin\u2010Necker Paris France"},{"name":"URC Tarnier Hospital France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brice","family":"Fresneau","sequence":"additional","affiliation":[{"name":"Department of Children and Adolescents Oncology Gustave Roussy Villejuif France"},{"name":"Paris\u2010Saclay University CESP INSERM Villejuif France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sophie","family":"Piperno\u2010Neumann","sequence":"additional","affiliation":[{"name":"Medical Oncology Department Institut Curie Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nathalie","family":"Gaspar","sequence":"additional","affiliation":[{"name":"Department of Children and Adolescents Oncology Gustave Roussy Villejuif France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nad\u00e8ge","family":"Corradini","sequence":"additional","affiliation":[{"name":"Pediatric Oncology Department Mother\u2010Children Hospital Nantes France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean\u2010Claude","family":"Gentet","sequence":"additional","affiliation":[{"name":"Pediatric Oncology Department La Timone Children's Hospital Marseille France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Perrine","family":"Marec Berard","sequence":"additional","affiliation":[{"name":"Pediatric Oncology Department Institute of Pediatric Hematology and Oncology\u2014L\u00e9on B\u00e9rard Anticancer Center Lyon France"},{"name":"Oncology Department Institut Curie Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Val\u00e9rie","family":"Laurence","sequence":"additional","affiliation":[{"name":"Medical Oncology Department Institut Curie Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pascale","family":"Schneider","sequence":"additional","affiliation":[{"name":"Pediatric Hemato\u2010Oncology Department University Hospital Rouen France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natacha","family":"Entz\u2010Werle","sequence":"additional","affiliation":[{"name":"Pediatric Oncology Department CHU Hautepierre Strasbourg France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"H\u00e9l\u00e8ne","family":"Pacquement","sequence":"additional","affiliation":[{"name":"Medical Oncology Department Institut Curie Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fr\u00e9d\u00e9ric","family":"Millot","sequence":"additional","affiliation":[{"name":"CIC\u20101402 INSERM Poitiers France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sophie","family":"Taque","sequence":"additional","affiliation":[{"name":"Department of Pediatric Hemato\u2010Oncology University Hospital Rennes France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claire","family":"Freycon","sequence":"additional","affiliation":[{"name":"Pediatric Department The Child and Family Hospital University Hospital Grenoble France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cyril","family":"Lervat","sequence":"additional","affiliation":[{"name":"Pediatric Oncology Unit Centre Oscar Lambret Lille France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie C\u00e9cile","family":"Le Deley","sequence":"additional","affiliation":[{"name":"Paris\u2010Saclay University CESP INSERM Villejuif France"},{"name":"Biostatistics Unit Gustave Roussy Villejuif France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C\u00e9line","family":"Mahier Ait Oukhatar","sequence":"additional","affiliation":[{"name":"UNICANCER Sarcoma Group Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laurence","family":"Brugieres","sequence":"additional","affiliation":[{"name":"Department of Children and Adolescents Oncology Gustave Roussy Villejuif France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gw\u00e9na\u00ebl","family":"Le Teuff","sequence":"additional","affiliation":[{"name":"Paris\u2010Saclay University CESP INSERM Villejuif France"},{"name":"Biostatistics Unit Gustave Roussy Villejuif France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Na\u00efm","family":"Bouazza","sequence":"additional","affiliation":[{"name":"EA 7323 Universit\u00e9 Paris Descartes Sorbonne Paris Cit\u00e9 Paris France"},{"name":"CIC\u20101419 Inserm Cochin\u2010Necker Paris France"},{"name":"URC Tarnier Hospital France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"for the Sarcoma Group of UNICANCER","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2018,5,23]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2014.59.4895"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.1994.12.7.1443"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1002\/cncr.20152"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1002\/pbc.10443"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/tpj.2012.37"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1097\/FTD.0b013e31823615e1"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1097\/FTD.0b013e3181945624"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1007\/s13318-016-0338-1"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1080\/02841860510029770"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.2174\/138920009789375414"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V100.10.3832"},{"key":"e_1_2_8_13_1","first-page":"292043","article-title":"Influence of methylenetetrahydrofolate reductase C677T, A1298C, and G80A polymorphisms on the survival of pediatric patients with acute lymphoblastic leukemia","volume":"2012","author":"Deus DMV","year":"2012","journal-title":"Leuk Res Treat"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0082681"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1097\/FPC.0b013e32835c3b24"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2012-08-452839"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2008.20.4156"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.clpt.2006.08.012"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2006-10-054528"},{"issue":"5","key":"e_1_2_8_20_1","doi-asserted-by":"crossref","first-page":"823","DOI":"10.1016\/S0090-9556(25)08168-1","article-title":"Effect of anticancer drugs on the glucuronidation of 3\u2019\u2010azido\u20103\u2019\u2010deoxythymidine in human liver microsomes","volume":"21","author":"Rajaonarison JF","year":"1993","journal-title":"Drug Metab Dispos Biol Fate Chem"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1002\/pbc.23074"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1038\/jid.2008.16"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.5045\/br.2016.51.1.50"},{"key":"e_1_2_8_24_1","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.11543"},{"key":"e_1_2_8_25_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0026091"},{"key":"e_1_2_8_26_1","doi-asserted-by":"publisher","DOI":"10.7314\/APJCP.2013.14.8.4595"},{"key":"e_1_2_8_27_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(16)30096-1"},{"key":"e_1_2_8_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejca.2017.09.036"},{"key":"e_1_2_8_29_1","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2008030287"},{"key":"e_1_2_8_30_1","doi-asserted-by":"publisher","DOI":"10.1186\/1472-6750-14-60"},{"key":"e_1_2_8_31_1","unstructured":"dbSNP Home Page.https:\/\/www-ncbi-nlm-nih-gov.gate2.inist.fr\/projects\/SNP\/. Updated October 6 2017. Accessed January 10 2018."},{"key":"e_1_2_8_32_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.csda.2004.07.002"},{"key":"e_1_2_8_33_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmpb.2007.12.002"},{"key":"e_1_2_8_34_1","doi-asserted-by":"publisher","DOI":"10.1208\/s12248-011-9255-z"},{"key":"e_1_2_8_35_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.pharmtox.48.113006.094708"},{"key":"e_1_2_8_36_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcph.488"},{"key":"e_1_2_8_37_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejca.2017.09.036"},{"key":"e_1_2_8_38_1","doi-asserted-by":"publisher","DOI":"10.1097\/CAD.0b013e3282f21376"},{"key":"e_1_2_8_39_1","doi-asserted-by":"publisher","DOI":"10.4103\/0366-6999.147829"},{"key":"e_1_2_8_40_1","doi-asserted-by":"publisher","DOI":"10.1124\/dmd.111.038794"},{"key":"e_1_2_8_41_1","doi-asserted-by":"publisher","DOI":"10.1158\/1535-7163.MCT-09-0668"},{"key":"e_1_2_8_42_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.molpharmaceut.7b00308"},{"key":"e_1_2_8_43_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.ki.5002645"},{"key":"e_1_2_8_44_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00280-009-1221-4"},{"key":"e_1_2_8_45_1","doi-asserted-by":"publisher","DOI":"10.1158\/1535-7163.MCT-08-0768"}],"container-title":["The Journal of Clinical Pharmacology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fjcph.1252","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/accp1.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/jcph.1252","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,7,4]],"date-time":"2025-07-04T18:21:06Z","timestamp":1751653266000},"score":1,"resource":{"primary":{"URL":"https:\/\/accp1.onlinelibrary.wiley.com\/doi\/10.1002\/jcph.1252"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,5,23]]},"references-count":44,"journal-issue":{"issue":"12","published-print":{"date-parts":[[2018,12]]}},"alternative-id":["10.1002\/jcph.1252"],"URL":"https:\/\/doi.org\/10.1002\/jcph.1252","archive":["Portico"],"relation":{},"ISSN":["0091-2700","1552-4604"],"issn-type":[{"value":"0091-2700","type":"print"},{"value":"1552-4604","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,5,23]]},"assertion":[{"value":"2018-01-23","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2018-04-08","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2018-05-23","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}