{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T10:05:18Z","timestamp":1753869918958,"version":"3.41.2"},"reference-count":9,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2024,6,12]],"date-time":"2024-06-12T00:00:00Z","timestamp":1718150400000},"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":["Pediatric Blood &amp; Cancer"],"published-print":{"date-parts":[[2024,9]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Alterations in the ALK (anaplastic lymphoma kinase) gene play a critical role in pathogenesis of anaplastic large cell lymphoma (ALCL). Crizotinib is a small molecule competitive inhibitor of ALK, ROS1, and MET kinases and was approved for pediatric patients with ALK\u2010positive relapsed or refractory, systemic ALCL, and ALK\u2010positive unresectable, recurrent, or refractory inflammatory myofibroblastic tumors (IMT).<\/jats:p><\/jats:sec><jats:sec><jats:title>Procedure<\/jats:title><jats:p>Crizotinib data from pediatric patients with relapsed or refractory solid tumors, IMT, or ALCL were included in the analyses. All patients received crizotinib orally at doses ranging from 100 to 365\u00a0mg\/m<jats:sup>2<\/jats:sup> twice daily (BID). PopPK analyses were conducted to characterize crizotinib disposition in pediatric patients. Exposure\u2013response (ER) safety and antitumor analyses were conducted to characterize relationships between crizotinib dose or exposure with safety and antitumor activity endpoints of interest.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The population pharmacokinetic (popPK), ER safety, and ER antitumor analysis included 98, 110, and 36 pediatric patients, respectively. A one\u2010compartment pharmacokinetic model with allometric scaling, first\u2010order elimination, and first\u2010order absorption with lag time adequately described the data. Natural log\u2010transformed model\u2010predicted crizotinib AUC<jats:sub>ss<\/jats:sub> (steady\u2010state area under the concentration\u2013time curve) demonstrated a significant, positive relationship with Grade \u22653 NEUTROPENIA and Any Grade VISION DISORDER. Crizotinib dose demonstrated a positive relationship with objective response rate.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>No significant differences in PK were identified across a wide range of ages or across tumor types, suggesting body surface area (BSA)\u2010based dosing adequately adjusted for differences in patient size to achieve similar systemic crizotinib exposures across young children and adolescent pediatric patients. None of the myelosuppressive events except Grade \u22653 NEUTROPENIA had significant relationships identified with crizotinib dose or exposure, suggesting crizotinib is a tolerable treatment with less hematological toxicity than traditional chemotherapy regimens for pediatric patients with ALK\u2010mutated cancers. Results from the presented analyses support the pediatric dosing recommendations in the product label.<\/jats:p><\/jats:sec>","DOI":"10.1002\/pbc.31139","type":"journal-article","created":{"date-parts":[[2024,6,13]],"date-time":"2024-06-13T04:23:23Z","timestamp":1718252603000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Population modeling analyses of crizotinib in pediatric patients with ALK\u2010positive advanced cancers"],"prefix":"10.1002","volume":"71","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8774-826X","authenticated-orcid":false,"given":"Li","family":"Jerry","sequence":"first","affiliation":[{"name":"Clinical Pharmacology Pfizer Inc.  New York New York USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lin","family":"Swan","sequence":"additional","affiliation":[{"name":"Clinical Pharmacology Neurocrine Biosciences  San Diego California USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nickens","family":"Dana","sequence":"additional","affiliation":[{"name":"Clinical Pharmacology Pfizer Inc.  New York New York USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Frank M.","family":"Balis","sequence":"additional","affiliation":[{"name":"Department of Pediatrics The Children's Hospital of Philadelphia Philadelphia Pennsylvania USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2963-5638","authenticated-orcid":false,"given":"Emily","family":"Greengard","sequence":"additional","affiliation":[{"name":"Department of Pediatrics University of Minnesota Minneapolis Minnesota USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xu","family":"Huiping","sequence":"additional","affiliation":[{"name":"Clinical Pharmacology Pfizer Inc.  New York New York USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2024,6,12]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00280-016-3220-6"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcp.10472"},{"key":"e_1_2_8_4_1","unstructured":"Xalkori [package insert].Pfizer Inc.; Published July 2022. Accessed December 10 2023.https:\/\/www.accessdata.fda.gov\/drugsatfda_docs\/label\/2022\/202570s033lbl.pdf"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-20-4224"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajh.25043"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2017.73.4830"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1096-911X(199903)32:3<225::AID-MPO12>3.0.CO;2-N"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1097\/00043426-200101000-00008"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.1994.12.3.544"}],"container-title":["Pediatric Blood &amp; Cancer"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/pbc.31139","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,7,25]],"date-time":"2024-07-25T03:36:03Z","timestamp":1721878563000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/pbc.31139"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,6,12]]},"references-count":9,"journal-issue":{"issue":"9","published-print":{"date-parts":[[2024,9]]}},"alternative-id":["10.1002\/pbc.31139"],"URL":"https:\/\/doi.org\/10.1002\/pbc.31139","archive":["Portico"],"relation":{},"ISSN":["1545-5009","1545-5017"],"issn-type":[{"type":"print","value":"1545-5009"},{"type":"electronic","value":"1545-5017"}],"subject":[],"published":{"date-parts":[[2024,6,12]]},"assertion":[{"value":"2024-02-08","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-05-24","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-06-12","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e31139"}}