{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,2]],"date-time":"2026-04-02T11:35:15Z","timestamp":1775129715127,"version":"3.50.1"},"reference-count":16,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2020,10,11]],"date-time":"2020-10-11T00:00:00Z","timestamp":1602374400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","award":["#P30 CA008748"],"award-info":[{"award-number":["#P30 CA008748"]}],"id":[{"id":"10.13039\/100000054","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":[[2021,4]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Pexidartinib is a kinase inhibitor that induces tumor response and improvements in symptoms and functional outcomes in adult patients with symptomatic tenosynovial giant cell tumor (TGCT). A population pharmacokinetic (PK) model for pexidartinib and its metabolite, ZAAD, was developed, and effects of demographic and clinical factors on the PK of pexidartinib and ZAAD were estimated. The analysis included pooled data from 7 studies in healthy volunteers (N\u00a0= 159) and 2 studies in patients with TGCT or other solid tumors (N\u00a0= 216). A structural 2\u2010compartment model with sequential zero\u2010 and first\u2010order absorption and lag time, and linear elimination from the central compartment adequately described pexidartinib and ZAAD PKs. Clearance of pexidartinib was estimated at 5.83 L\/h in a typical patient with reference covariates (male, non\u2010Asian, weight\u00a0= 80\u00a0kg, creatinine clearance \u226590\u00a0mL\/min, aspartate aminotransferase \u226480\u00a0U\/L, and total bilirubin \u226420.5\u00a0\u03bcmol\/L). In the covariate analysis, Asians and healthy subjects had modestly lower pexidartinib exposure (21% decrease each) in terms of steady\u2010state area under the curve values from 0 to 24 hours (AUC<jats:sub>0\u201024,ss<\/jats:sub>). Effects of body weight, sex, and hepatic function parameters on pexidartinib AUC<jats:sub>0\u201024,ss<\/jats:sub> were generally &lt;20%. Patients with TGCT with mild renal impairment were predicted to have approximately 23% higher AUC<jats:sub>0\u201024,ss<\/jats:sub> than those with normal renal function. The effects of covariates on ZAAD exposure were similar to those on pexidartinib. These results indicate small and generally clinically nonmeaningful effects of patient demographic and clinical characteristics on pexidartinib and ZAAD PK profiles.<\/jats:p>","DOI":"10.1002\/jcph.1753","type":"journal-article","created":{"date-parts":[[2020,10,12]],"date-time":"2020-10-12T03:42:56Z","timestamp":1602474176000},"page":"480-492","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Population Pharmacokinetic Analysis of Pexidartinib in Healthy Subjects and Patients With Tenosynovial Giant Cell Tumor or Other Solid Tumors"],"prefix":"10.1002","volume":"61","author":[{"given":"Ophelia","family":"Yin","sequence":"first","affiliation":[{"name":"Quantitative Clinical Pharmacology and Translational Sciences Daiichi Sankyo, Inc.  Basking Ridge New Jersey USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrew J.","family":"Wagner","sequence":"additional","affiliation":[{"name":"Dana\u2010Farber Cancer Institute  Boston Massachusetts USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jia","family":"Kang","sequence":"additional","affiliation":[{"name":"Metrum Research Group  Tariffville Connecticut USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"William","family":"Knebel","sequence":"additional","affiliation":[{"name":"Metrum Research Group  Tariffville Connecticut USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hamim","family":"Zahir","sequence":"additional","affiliation":[{"name":"Quantitative Clinical Pharmacology and Translational Sciences Daiichi Sankyo, Inc.  Basking Ridge New Jersey USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michiel","family":"van de Sande","sequence":"additional","affiliation":[{"name":"Leiden University Medical Center  Leiden The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"William D.","family":"Tap","sequence":"additional","affiliation":[{"name":"Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College  New York New York USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hans","family":"Gelderblom","sequence":"additional","affiliation":[{"name":"Leiden University Medical Center  Leiden The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"John H.","family":"Healey","sequence":"additional","affiliation":[{"name":"Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College  New York New York USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dale","family":"Shuster","sequence":"additional","affiliation":[{"name":"Global Oncology R&amp;D Daiichi Sankyo, Inc.  Basking Ridge New Jersey USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Silvia","family":"Stacchiotti","sequence":"additional","affiliation":[{"name":"Fondazione IRCCS Istituto Nazionale dei Tumori  Milan Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2020,10,11]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1411366"},{"key":"e_1_2_11_3_1","unstructured":"2020 Daiichi Sankyo Inc Basking Ridge NJ"},{"key":"e_1_2_11_4_1","unstructured":"DK Vandell AG M Desai Effect of dose strength food and pH modifiers on the pharmacokinetics of the multi\u2010kinase inhibitor pexidartinib"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(19)30764-0"},{"key":"e_1_2_11_6_1","unstructured":"GastonguayMR.Full covariate models as an alternative to methods relying on statistical significance for inferences about covariate effects: a review of methodology and 42 case studies. PAGE Conference. June 2011. Athens Greece. Abstract 2229.www.page-meeting.org\/?abstract=2229."},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1159\/000180580"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1023\/A:1011555016423"},{"key":"e_1_2_11_9_1","unstructured":"US Food and Drug Administration.Center for Drug Evaluation and Research. Guidance Document. Pharmacokinetics in patients with impaired renal function\u2014study design data analysis and impact on dosing and labeling.https:\/\/www.fda.gov\/regulatory-information\/search-fda-guidance-documents\/pharmacokinetics-patients-impaired-renal-function-study-design-data-analysis-and-impact-dosing-and. Published March 2010. Accessed June 4 2020."},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-16-0449"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2017.75.8482"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0121451"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1097-0258(19960229)15:4<361::AID-SIM168>3.0.CO;2-4"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.1208\/aapsj080364"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.1111\/bcp.12323"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.1177\/1758835919854238"},{"key":"e_1_2_11_17_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10637-019-00745-z"}],"container-title":["The Journal of Clinical Pharmacology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/jcph.1753","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/jcph.1753","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/jcph.1753","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/accp1.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/jcph.1753","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,1]],"date-time":"2023-09-01T08:10:38Z","timestamp":1693555838000},"score":1,"resource":{"primary":{"URL":"https:\/\/accp1.onlinelibrary.wiley.com\/doi\/10.1002\/jcph.1753"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,10,11]]},"references-count":16,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2021,4]]}},"alternative-id":["10.1002\/jcph.1753"],"URL":"https:\/\/doi.org\/10.1002\/jcph.1753","archive":["Portico"],"relation":{},"ISSN":["0091-2700","1552-4604"],"issn-type":[{"value":"0091-2700","type":"print"},{"value":"1552-4604","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,10,11]]},"assertion":[{"value":"2020-06-23","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2020-09-03","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2020-10-11","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}