{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,23]],"date-time":"2026-03-23T12:25:35Z","timestamp":1774268735955,"version":"3.50.1"},"reference-count":25,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2025,7,16]],"date-time":"2025-07-16T00:00:00Z","timestamp":1752624000000},"content-version":"vor","delay-in-days":15,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2025,7,1]],"date-time":"2025-07-01T00:00:00Z","timestamp":1751328000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clinical Translational Sci"],"published-print":{"date-parts":[[2025,7]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    QTc prolongation has been associated with torsades de pointes (TdP) and also with other cardiac diseases. We investigated the effect of ipatasertib, a selective serine\/threonine kinase (AKT, protein kinase B) inhibitor, on preclinical models of QTc prolongation as well as across two clinical studies. Preclinical in\u00a0vitro studies suggested that ipatasertib and its metabolite, M1, were unlikely to inhibit human Ether\u2010\u00e0\u2010go\u2010go\u2010Related Gene (hERG) channels at the clinically relevant dose. However, clinical evaluation of ipatasertib and its metabolite in the first\u2010in\u2010human study PAM4743g suggested a mild prolongation of the QTc interval, but the effect was delayed, where the maximum change from baseline QTc seemed to occur 2\u20134\u2009h after time to maximum drug exposure (T\n                    <jats:sub>max<\/jats:sub>\n                    ). QTc prolongation was further evaluated in a second Phase 1b study, GP42658, with pretreatment QTc measurement for baseline correction and intensive post\u2010baseline QTcF measurements at steady state. The results showed a delayed effect, where peak \u0394QTcF occurred 2\u20134\u2009h after T\n                    <jats:sub>max<\/jats:sub>\n                    with a mean of 10.9\u2009ms and an upper 95% CI of 19.1\u2009ms. Although a delayed effect was observed, the overall magnitude of the QTc effect was not large, and taken together, ipatasertib may not pose a substantial proarrhythmic risk (i.e., mean increase of &gt;\u200920\u2009ms) at the intended therapeutic dose of 400\u2009mg.\n                  <\/jats:p>","DOI":"10.1111\/cts.70298","type":"journal-article","created":{"date-parts":[[2025,7,17]],"date-time":"2025-07-17T05:45:27Z","timestamp":1752731127000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Quantifying Risk of Delayed QT Prolongation of Ipatasertib in Preclinical and Clinical Studies in Cancer Patients"],"prefix":"10.1111","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4215-2198","authenticated-orcid":false,"given":"Victor","family":"Poon","sequence":"first","affiliation":[{"name":"Genentech  South San Francisco California 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USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9043-5336","authenticated-orcid":false,"given":"Rucha","family":"Sane","sequence":"additional","affiliation":[{"name":"Genentech  South San Francisco California USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2025,7,16]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2005.08.067"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11096\u2010016\u20100414\u20102"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.5152\/akd.2015.5875"},{"issue":"7","key":"e_1_2_9_5_1","first-page":"473","article-title":"Drug\u2010Induced QT Prolongation and Torsades de Pointes","volume":"42","author":"Li M.","year":"2017","journal-title":"Pharmacy and 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https:\/\/www.fda.gov\/regulatory\u2010information\/search\u2010fda\u2010guidance\u2010documents\/e14\u2010and\u2010s7b\u2010clinical\u2010and\u2010nonclinical\u2010evaluation\u2010qtqtc\u2010interval\u2010prolongation\u2010and\u2010proarrhythmic."},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.3390\/pharmaceutics14102101"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-16-0512"},{"key":"e_1_2_9_15_1","unstructured":"Center for Drug Evaluation and Research \u201cS7A Safety Pharmacology Studies for Human Pharmaceuticals \u201d(2001) https:\/\/www.fda.gov\/regulatory\u2010information\/search\u2010fda\u2010guidance\u2010documents\/s7a\u2010safety\u2010pharmacology\u2010studies\u2010human\u2010pharmaceuticals."},{"key":"e_1_2_9_16_1","unstructured":"Center for Drug Evaluation and Research \u201cNonclinical Evaluation of the Potential for Delayed Repolarization (QT Interval Prolongation) by Human Pharmaceuticals \u201d(2005) 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