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Significant heart rate (HR) change has been associated with certain classes of oncology drugs and can result in over\u2010 or underestimation of the true QT prolongation risk. Because oncology early clinical trials typically lack a placebo control arm or time\u2010matched, treatment\u2010free baseline electrocardiogram collection, significant HR change brings additional challenges to C\u2010QTc analysis in the oncology setting. In this work, a spline\u2010based correction method (QTcSPL) was explored to mitigate the impact of HR changes in giredestrant C\u2010QTc analysis. Giredestrant is a selective estrogen receptor degrader being developed for the treatment of patients with estrogen receptor\u2010positive (ER+) breast cancer. A dose\u2010related HR decrease has been observed in patients under giredestrant treatment, with significant reductions (&gt;10\u00a0bpm) observed at supratherapeutic doses. The QTcSPL method demonstrated superior functionality to reduce the correlation between QTc and HR as compared with the Fridericia correction (QTcF). The effect of giredestrant exposure on QTc was evaluated at the clinical dose of 30\u2009mg and supratherapeutic dose of 100\u2009mg based on a prespecified linear mixed effect model. The upper 90% confidence interval of \u0394QTcSPL and \u0394QTcF were below the 10\u00a0ms at both clinical and supratherapeutic exposures, suggesting giredestrant has a low risk of QT prolongation at clinically relevant concentrations. This work demonstrated the use case of QTcSPL to address HR confounding challenges in the context of oncology drug development for the first time.<\/jats:p>","DOI":"10.1111\/cts.13491","type":"journal-article","created":{"date-parts":[[2023,2,11]],"date-time":"2023-02-11T09:45:09Z","timestamp":1676108709000},"page":"823-834","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Concentration <scp>QTc<\/scp> analysis of giredestrant: Overcoming <scp>QT<\/scp>\/heart rate confounding in the presence of drug\u2010induced heart rate changes"],"prefix":"10.1111","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9215-408X","authenticated-orcid":false,"given":"Logan","family":"Brooks","sequence":"first","affiliation":[{"name":"Clinical Pharmacology Genentech, Inc.  South San Francisco California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Dolton","sequence":"additional","affiliation":[{"name":"Clinical Pharmacology Genentech, Inc.  South San Francisco California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jurgen","family":"Langenhorst","sequence":"additional","affiliation":[{"name":"Pharmetheus AB  Uppsala Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4967-3831","authenticated-orcid":false,"given":"Kenta","family":"Yoshida","sequence":"additional","affiliation":[{"name":"Clinical Pharmacology Genentech, Inc.  South San Francisco California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi Ting (Kayla)","family":"Lien","sequence":"additional","affiliation":[{"name":"Clinical Pharmacology Genentech, Inc.  South San Francisco California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vikram","family":"Malhi","sequence":"additional","affiliation":[{"name":"Clinical Pharmacology Genentech, Inc.  South San Francisco California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chunze","family":"Li","sequence":"additional","affiliation":[{"name":"Clinical Pharmacology Genentech, Inc.  South San Francisco California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pablo","family":"Perez\u2010Moreno","sequence":"additional","affiliation":[{"name":"Product Development Oncology Genentech, Inc.  South San Francisco California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"Bond","sequence":"additional","affiliation":[{"name":"Product Development Oncology Genentech, Inc.  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