{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T23:58:03Z","timestamp":1790035083398,"version":"4.0.1"},"reference-count":20,"publisher":"Wiley","issue":"11","license":[{"start":{"date-parts":[[2025,6,8]],"date-time":"2025-06-08T00:00:00Z","timestamp":1749340800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":["accp1.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Clinical Pharma"],"published-print":{"date-parts":[[2025,11]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Fruquintinib is a highly selective oral inhibitor of vascular endothelial growth factor receptors 1, 2, and 3, approved by the US Food and Drug Administration and the European Commission for the treatment of previously treated metastatic colorectal cancer (mCRC), regardless of biomarker status. This study used concentration QT interval (C\u2010QTc) modeling, utilizing data from the phase 3 FRESCO\u20102 study (NCT04322539) in which patients with mCRC received fruquintinib 5 mg, once daily, or matching placebo in a 28\u2010day cycle, to evaluate the potential of fruquintinib to delay cardiac repolarization. The primary objectives were to assess the relationship between change from baseline in the QTc and plasma concentrations of fruquintinib and its metabolite M11, and to predict placebo\u2010corrected change from baseline in the corrected QT interval (\u0394\u0394QTc) associated with clinically relevant fruquintinib or M11 concentrations. The C\u2010QTc analysis was conducted using 1456 time\u2010matched concentration\u2010change from baseline in the population\u2010based corrected QT interval (\u0394QTcP) pairs from 205 patients (fruquintinib n = 137; placebo n = 68). The final C\u2010QTc model was a linear mixed\u2010effects model with the effect of M11 concentration on \u0394QTcP. This model estimated that the upper bounds of the 90% CI of the mean \u0394\u0394QTcP at steady\u2010state geometric mean (GM) M11 C\n                    <jats:sub>max,<\/jats:sub>\n                    and twice the GM M11 C\n                    <jats:sub>max<\/jats:sub>\n                    were 0.0537 and 4.00 ms, respectively. Additional C\u2010QTc analysis, including only fruquintinib concentrations, showed no relationship between \u0394QTcP and fruquintinib concentrations. The analysis indicated that fruquintinib administered at the approved clinical dose is not anticipated to cause clinically meaningful QT prolongation.\n                  <\/jats:p>","DOI":"10.1002\/jcph.70051","type":"journal-article","created":{"date-parts":[[2025,6,9]],"date-time":"2025-06-09T01:04:08Z","timestamp":1749431048000},"page":"1411-1419","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Assessment of the Effects of Fruquintinib on Cardiac Safety in Patients with Metastatic Colorectal Cancer"],"prefix":"10.1002","volume":"65","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0319-1327","authenticated-orcid":false,"given":"Xiaofei","family":"Zhou","sequence":"first","affiliation":[{"name":"Takeda Development Center Americas, Inc. (TDCA)  Cambridge MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alice","family":"Toms","sequence":"additional","affiliation":[{"name":"Certara, Radnor  PA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dave","family":"Morton","sequence":"additional","affiliation":[{"name":"Certara, Radnor  PA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaohui","family":"Wang","sequence":"additional","affiliation":[{"name":"Certara, Radnor  PA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7373-5660","authenticated-orcid":false,"given":"Adekemi","family":"Taylor","sequence":"additional","affiliation":[{"name":"Certara, Radnor  PA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arvind","family":"Dasari","sequence":"additional","affiliation":[{"name":"University of Texas MD Anderson Cancer Center  Houston TX USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neeraj","family":"Gupta","sequence":"additional","affiliation":[{"name":"Takeda Development Center Americas, Inc. (TDCA)  Cambridge MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caly","family":"Chien","sequence":"additional","affiliation":[{"name":"HUTCHMED International Corporation  Florham Park NJ USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,6,8]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.4161\/15384047.2014.964087"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00280-016-3069-8"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00280-017-3394-6"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2018.7855"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40265-018-0998-z"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(23)00772-9"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2023.41.4_suppl.67"},{"key":"e_1_2_9_9_1","unstructured":"FRUZAQLA\u2122 (fruquintinib) prescribing information.Takeda Pharmaceuticals. Accessed January 25 2024.https:\/\/www.accessdata.fda.gov\/drugsatfda_docs\/label\/2023\/217564s000lbl.pdf"},{"key":"e_1_2_9_10_1","unstructured":"FRUZAQLA\u2122 (fruquintinib) summary of product characteristics.Takeda Pharmaceuticals. Accessed July 12 2024.https:\/\/www.ema.europa.eu\/en\/documents\/product\u2010information\/fruzaqla\u2010epar\u2010product\u2010information_en.pdf"},{"key":"e_1_2_9_11_1","unstructured":"Guidance for industry: E14 clinical evaluation of QT\/QTc interval prolongation and proarrhythmic potential for non\u2010antiarrhythmic drugs.US Food and Drug Administration. October2012. 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Accessed January 26 2024.https:\/\/www.fda.gov\/regulatory\u2010information\/search\u2010fda\u2010guidance\u2010documents\/e14\u2010clinical\u2010evaluation\u2010qtqtc\u2010interval\u2010prolongation\u2010and\u2010proarrhythmic\u2010potential\u2010non\u2010antiarrhythmic\u20101"},{"key":"e_1_2_9_16_1","unstructured":"ICH E14 guideline: The clinical evaluation of QT\/QTc interval prolongation and proarrhythmic potential for non\u2010antiarrhythmic drugs.E14 Implementation Working Group.2015. Accessed April 14 2025.https:\/\/database.ich.org\/sites\/default\/files\/E14_Q%26As_R3_Q%26As.pdf"},{"key":"e_1_2_9_17_1","unstructured":"R Core Team.R: A language and environment for statistical computing. R Foundation for Statistical Computing;2022. 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