{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,5]],"date-time":"2025-12-05T12:28:55Z","timestamp":1764937735150,"version":"3.41.2"},"reference-count":5,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2024,5,3]],"date-time":"2024-05-03T00:00:00Z","timestamp":1714694400000},"content-version":"vor","delay-in-days":2,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clinical Translational Sci"],"published-print":{"date-parts":[[2024,5]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Sitravatinib (MGCD516) is an orally available, small molecule, tyrosine kinase inhibitor that has been evaluated in patients with advanced solid tumors. Concentration\u2010corrected QT interval (QTc; C\u2010QTc) modeling was undertaken, using 767 matched concentration\u2010ECG observations from 187 patients across two clinical studies in patients with advanced solid malignancies, across a dose range of 10\u2013200\u2009mg, via a linear mixed\u2010effects (LME) model. The effect on heart rate (HR)\u2010corrected QT interval via Fridericia's correction method (QTcF) at the steady\u2010state maximum concentration (<jats:italic>C<\/jats:italic><jats:sub>max,ss<\/jats:sub>) for the sitravatinib proposed therapeutic dosing regimen (100\u2009mg malate once daily [q.d.]) without and with relevant intrinsic and extrinsic factors were predicted. No significant changes in HR from baseline were observed. Hysteresis between sitravatinib plasma concentration and change in QTcF from baseline (\u0394QTcF) was not observed. There was no significant relationship between sitravatinib plasma concentration and \u0394QTcF. The final C\u2010QTc model predicted a mean (90% confidence interval [CI]) \u0394QTcF of 3.92 (1.95\u20135.89) ms and 2.94 (0.23\u20136.10) ms at the proposed therapeutic dosing regimen in patients with normal organ function (best case scenario) and patients with hepatic impairment (worst\u2010case scenario), respectively. The upper bounds of the 90% CIs were below the regulatory threshold of concern of 10\u2009ms. The results of the described C\u2010QTc analysis, along with corroborating results from nonclinical safety pharmacology studies, indicate that sitravatinib has a low risk of QTc interval prolongation at the proposed therapeutic dose of 100\u2009mg malate q.d.<\/jats:p>","DOI":"10.1111\/cts.13808","type":"journal-article","created":{"date-parts":[[2024,5,3]],"date-time":"2024-05-03T12:35:15Z","timestamp":1714739715000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["<scp>Concentration\u2010QTc<\/scp> modeling of sitravatinib in patients with advanced solid malignancies"],"prefix":"10.1111","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9246-7753","authenticated-orcid":false,"given":"Adam","family":"Dickinson","sequence":"first","affiliation":[{"name":"Mirati Therapeutics Inc  San Diego California USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yong","family":"Liu","sequence":"additional","affiliation":[{"name":"Mirati Therapeutics Inc  San Diego California USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4568-3143","authenticated-orcid":false,"given":"Artem","family":"Uvarov","sequence":"additional","affiliation":[{"name":"Certara Drug Development Solutions  Princeton New Jersey USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3723-4006","authenticated-orcid":false,"given":"Thomas","family":"Peyret","sequence":"additional","affiliation":[{"name":"Certara Drug Development Solutions  Princeton New Jersey USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9820-5116","authenticated-orcid":false,"given":"J. F.","family":"Marier","sequence":"additional","affiliation":[{"name":"Certara Drug Development Solutions  Princeton New Jersey USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Curtis","family":"Chin","sequence":"additional","affiliation":[{"name":"Mirati Therapeutics Inc  San Diego California USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7187-7307","authenticated-orcid":false,"given":"Jonathan Q.","family":"Tran","sequence":"additional","affiliation":[{"name":"Mirati Therapeutics Inc  San Diego California USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2024,5,3]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10637-022-01274-y"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.annonc.2023.10.004"},{"key":"e_1_2_9_4_1","unstructured":"ICH\/FDA Guidance for Industry: E14 Clinical Evaluation of QT\/QTc Interval Prolongation and Proarrhythmic Potential for Non\u2010Antiarrhythmic Drug.2005.https:\/\/www.fda.gov\/files\/drugs\/published\/E14\u2010Clinical\u2010Evaluation\u2010of\u2010QT\u2010QTc\u2010Interval\u2010Prolongation\u2010and\u2010Proarrhythmic\u2010Potential\u2010for\u2010Non\u2010Antiarrhythmic\u2010Drugs.pdf. Accessed December 18 2023."},{"key":"e_1_2_9_5_1","unstructured":"ICH E14 and S7B clinical and nonclinical evaluation of QT\/QTc interval prolongation and proarrhythmic potential. Questions and answers.2022.https:\/\/www.fda.gov\/media\/161198\/download. Accessed December 18 2023"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10928-017-9558-5"}],"container-title":["Clinical and Translational Science"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/cts.13808","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,5,28]],"date-time":"2024-05-28T11:27:05Z","timestamp":1716895625000},"score":1,"resource":{"primary":{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/10.1111\/cts.13808"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,5]]},"references-count":5,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2024,5]]}},"alternative-id":["10.1111\/cts.13808"],"URL":"https:\/\/doi.org\/10.1111\/cts.13808","archive":["Portico"],"relation":{},"ISSN":["1752-8054","1752-8062"],"issn-type":[{"type":"print","value":"1752-8054"},{"type":"electronic","value":"1752-8062"}],"subject":[],"published":{"date-parts":[[2024,5]]},"assertion":[{"value":"2024-01-17","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-03-26","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-05-03","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e13808"}}