{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,29]],"date-time":"2026-05-29T14:46:55Z","timestamp":1780066015882,"version":"3.54.0"},"reference-count":24,"publisher":"Wiley","issue":"11","license":[{"start":{"date-parts":[[2024,11,12]],"date-time":"2024-11-12T00:00:00Z","timestamp":1731369600000},"content-version":"vor","delay-in-days":11,"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":[[2024,11]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Quizartinib prolongs QT interval through inhibition of the slow delayed rectifier potassium current (I<jats:sub>Ks<\/jats:sub>). We used non\u2010linear mixed\u2010effects modeling to explore the relationship between quizartinib and its pharmacologically active metabolite AC886 and the Fridericia\u2010corrected QT interval (QTcF) in newly diagnosed acute myeloid leukemia (AML) patients. We evaluated linear and non\u2010linear drug effect models, using triplicate QTcF measurements with available time\u2010matched pharmacokinetic samples from the Phase 3 QuANTUM\u2010First trial. The effect of intrinsic and extrinsic factors on model parameters was tested using stepwise covariate model building. Simulations were conducted to predict the change from baseline in QTcF (\u0394QTcF) at the maximum concentration at steady\u2010state (<jats:italic>C<\/jats:italic><jats:sub>max,ss<\/jats:sub>) for quizartinib maintenance daily doses of 30 and 60\u2009mg. The concentration\u2010QTcF (C\u2010QTcF) relationship was best described by a sigmoidal maximum effect model. After accounting for the effect of quizartinib, including AC886 concentrations did not further explain changes in QTcF. Circadian variations in QTcF were described using an empirical change from baseline based on clock times. Age and hypokalaemia were identified as statistically significant covariates on baseline QTcF; no covariates were found to impact the C\u2010QTcF relationship. The median model\u2010predicted \u0394QTcF at <jats:italic>C<\/jats:italic><jats:sub>max,ss<\/jats:sub> was 18.4\u2009ms (90% confidence interval (CI): 16.3\u201320.5) at 30\u2009mg and 24.1\u2009ms (90% CI: 21.4\u201326.6) at 60\u2009mg. In conclusion, in newly diagnosed AML patients, \u0394QTcF increased non\u2010linearly with increasing quizartinib concentrations. The predicted \u0394QTcF increase at <jats:italic>C<\/jats:italic><jats:sub>max,ss<\/jats:sub> supports the proposed dose adaptation based on observed QTcF and the dose reduction in case of strong cytochrome P450 3A (CYP3A) inhibitors coadministration.<\/jats:p>","DOI":"10.1111\/cts.70065","type":"journal-article","created":{"date-parts":[[2024,11,13]],"date-time":"2024-11-13T11:56:00Z","timestamp":1731498960000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Concentration\u2010<scp>QTcF<\/scp> analysis of quizartinib in patients with newly diagnosed <scp>FLT3<\/scp>\u2010internal\u2010tandem\u2010duplication\u2010positive acute myeloid leukemia"],"prefix":"10.1111","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7369-6649","authenticated-orcid":false,"given":"Pavan","family":"Vaddady","sequence":"first","affiliation":[{"name":"Quantitative Clinical Pharmacology Department Daiichi Sankyo, Inc.  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