{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T08:57:28Z","timestamp":1790758648188,"version":"4.1.0"},"reference-count":37,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2021,7,7]],"date-time":"2021-07-07T00:00:00Z","timestamp":1625616000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Intl Journal of Cancer"],"published-print":{"date-parts":[[2021,10,15]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Pemetrexed is an important component of first line treatment in patients with non\u2010squamous non\u2010small cell lung cancer. However, a limitation is the contraindication in patients with renal impairment due to hematological toxicity. Currently, it is unknown how to safely dose pemetrexed in these patients. The aim of our study was to elucidate the relationship between pemetrexed exposure and toxicity to support the development of a safe dosing regimen in patients with renal impairment. A population pharmacokinetic\/pharmacodynamic analysis was performed based on phase II study results in three patients with renal dysfunction, supplemented with data from 106 patients in early clinical studies. Findings were externally validated with data of different pemetrexed dosing regimens. Alternative dosing regimens were evaluated using the developed model. We found that pemetrexed toxicity was driven by the time above a toxicity threshold concentration. The threshold for vitamin\u2010supplemented patients was 0.110\u2009mg\/mL (95% CI: 0.092\u20100.146\u2009mg\/mL). It was observed that in patients with renal impairment (estimated glomerular filtration rate [eGFR]: &lt;45\u2009mL\/min) the approved dose of 500\u2009mg\/m<jats:sup>2<\/jats:sup> would yield a high probability of severe neutropenia in the range of 51.0% to 92.6%. A pemetrexed dose of 20\u2009mg for patients (eGFR: 20\u2009mL\/min) is shown to be neutropenic\u2010equivalent to the approved dose in patients with adequate renal function (eGFR: 90\u2009mL\/min), but would result in an approximately 13\u2010fold lower area under the concentration\u2010time curve. The pemetrexed exposure\u2010toxicity relationship is explained by a toxicity threshold and substantially different from previously thought. Without prophylaxis for toxicity, it is unlikely that a therapeutic dose can be safely administered to patients with renal impairment.<\/jats:p>","DOI":"10.1002\/ijc.33721","type":"journal-article","created":{"date-parts":[[2021,6,28]],"date-time":"2021-06-28T13:01:25Z","timestamp":1624885285000},"page":"1576-1584","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["Toxicity of pemetrexed during renal impairment explained\u2014Implications for safe treatment"],"prefix":"10.1002","volume":"149","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6399-2604","authenticated-orcid":false,"given":"Ren\u00e9 J.","family":"Boosman","sequence":"first","affiliation":[{"name":"Department of Pharmacy &amp; Pharmacology Antoni van Leeuwenhoek\u2014The Netherlands Cancer Institute  Amsterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas P. C.","family":"Dorlo","sequence":"additional","affiliation":[{"name":"Department of Pharmacy &amp; Pharmacology Antoni van Leeuwenhoek\u2014The Netherlands Cancer Institute  Amsterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nikki","family":"de Rouw","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Radboud Institute for Health Sciences Radboud University Medical Center  Nijmegen The Netherlands"},{"name":"Department of Pharmacy Jeroen Bosch Hospital  's\u2010Hertogenbosch The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacobus A.","family":"Burgers","sequence":"additional","affiliation":[{"name":"Department of Thoracic Oncology The Netherlands Cancer Institute  Amsterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne\u2010Marie C.","family":"Dingemans","sequence":"additional","affiliation":[{"name":"Department of Pulmonary Diseases, GROW\u2014School for Oncology and Developmental Biology Maastricht University Medical Centre  Maastricht The Netherlands"},{"name":"Department of Pulmonology Erasmus MC  Rotterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michel M.","family":"van den Heuvel","sequence":"additional","affiliation":[{"name":"Department of Pulmonology Radboud university medical center  Nijmegen The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lizza E. L.","family":"Hendriks","sequence":"additional","affiliation":[{"name":"Department of Pulmonary Diseases, GROW\u2014School for Oncology and Developmental Biology Maastricht University Medical Centre  Maastricht The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bonne","family":"Biesma","sequence":"additional","affiliation":[{"name":"Department of Pulmonary Diseases Jeroen Bosch Hospital  's Hertogenbosch The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joachim G. J. V.","family":"Aerts","sequence":"additional","affiliation":[{"name":"Department of Pulmonology Erasmus MC  Rotterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sander","family":"Croes","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacy &amp; Toxicology Maastricht University Medical Centre  Maastricht The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ron H. J.","family":"Mathijssen","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology Erasmus Medical Center Cancer Institute  Rotterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alwin D. R.","family":"Huitema","sequence":"additional","affiliation":[{"name":"Department of Pharmacy &amp; Pharmacology Antoni van Leeuwenhoek\u2014The Netherlands Cancer Institute  Amsterdam The Netherlands"},{"name":"Department of Clinical Pharmacy Utrecht University Medical Center, Utrecht University  Utrecht The Netherlands"},{"name":"Department of Pharmacology Princess M\u00e1xima Center for Pediatric Oncology  Utrecht The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rob","family":"ter Heine","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Radboud Institute for Health Sciences Radboud University Medical Center  Nijmegen The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2021,7,7]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1093\/annonc\/mdy275"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1093\/annonc\/mdv199"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jtho.2018.07.094"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00280-016-3078-7"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00280-005-0077-5"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2003.11.136"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2004.00.9720"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00408-008-9123-5"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.3892\/ol.2012.672"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1158\/078-0432.ccr-08-791"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00280-005-0035-2"},{"key":"e_1_2_9_13_1","unstructured":"CSDR.Available from:https:\/\/www.clinicalstudydatarequest.com\/Posting.aspx?ID=19619&GroupID=SUMMARIES. Accessed November 20 2019."},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00280-005-0036-1"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.7326\/0003-4819-150-9-200905050-00006"},{"issue":"1","key":"e_1_2_9_16_1","first-page":"1216","article-title":"Prediction of creatinine clearance from serum creatinine","volume":"16","author":"Cockcroft DW","year":"1976","journal-title":"Nepron"},{"issue":"3","key":"e_1_2_9_17_1","first-page":"605","article-title":"A phase I and pharmacokinetic study of LY231514, the multitargeted antifolate","volume":"4","author":"McDonald AC","year":"1998","journal-title":"Clin Cancer Res"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.995.13.11.2842"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1007\/s002800050992"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40262-020-00972-1"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2002.02.140"},{"key":"e_1_2_9_22_1","volume-title":"Common Toxicity Criteria for Adverse Events v4.03 (CTCAE)","author":"National Cancer Institute Cancer Therapy Evaluation Program","year":"2009"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM197709222971203"},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.lungcan.2020.11.028"},{"issue":"6","key":"e_1_2_9_25_1","first-page":"1116","article-title":"LY231514, a pyrrolo[2,3\u2010d]pyrimidine\u2010based antifolate that inhibits multiple folate\u2010requiring enzymes","volume":"57","author":"Shih C","year":"1997","journal-title":"Cancer Res"},{"key":"e_1_2_9_26_1","doi-asserted-by":"publisher","DOI":"10.1021\/jm00101a023"},{"key":"e_1_2_9_27_1","doi-asserted-by":"publisher","DOI":"10.1634\/theoncologist.9-5-482"},{"issue":"5","key":"e_1_2_9_28_1","first-page":"3235","article-title":"Role of folic acid in modulating the toxicity and efficacy of the multitargeted antifolate, LY231514","volume":"18","author":"Worzalla JF","year":"1998","journal-title":"Anticancer Res"},{"key":"e_1_2_9_29_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2020.00975"},{"key":"e_1_2_9_30_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.bjc.6605559"},{"key":"e_1_2_9_31_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI107362"},{"key":"e_1_2_9_32_1","doi-asserted-by":"publisher","DOI":"10.1634\/theoncologist.2015-0164"},{"key":"e_1_2_9_33_1","unstructured":"European Medicine Agency (EMA).Alimta: EPAR\u2014Scientific Discussion;2006."},{"key":"e_1_2_9_34_1","unstructured":"European Medicine Agency (EMA).Alimta: EPAR\u2014Product information;2009."},{"key":"e_1_2_9_35_1","unstructured":"European Medicine Agency (EMA).FILGRASTIM HEXAL\u2014Product Information;2019."},{"key":"e_1_2_9_36_1","doi-asserted-by":"publisher","DOI":"10.1016\/0002-9343(92)90088-s"},{"issue":"12","key":"e_1_2_9_37_1","first-page":"732","article-title":"Glucarpidase (voraxaze), a carboxypeptidase enzyme for methotrexate toxicity","volume":"38","author":"Rattu MA","year":"2013","journal-title":"P T"},{"issue":"4773","key":"e_1_2_9_38_1","article-title":"In vitro demonstration that pemetrexed is a good substrate for glucarpidase","volume":"67","author":"Auton T","year":"2007","journal-title":"Cancer Res"}],"container-title":["International Journal of Cancer"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ijc.33721","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/ijc.33721","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ijc.33721","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,8,16]],"date-time":"2023-08-16T23:20:53Z","timestamp":1692228053000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/ijc.33721"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,7,7]]},"references-count":37,"journal-issue":{"issue":"8","published-print":{"date-parts":[[2021,10,15]]}},"alternative-id":["10.1002\/ijc.33721"],"URL":"https:\/\/doi.org\/10.1002\/ijc.33721","archive":["Portico"],"relation":{},"ISSN":["0020-7136","1097-0215"],"issn-type":[{"value":"0020-7136","type":"print"},{"value":"1097-0215","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,7,7]]},"assertion":[{"value":"2021-04-02","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2021-05-27","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2021-07-07","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}