{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T16:14:22Z","timestamp":1753892062670,"version":"3.41.2"},"reference-count":23,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2024,8,12]],"date-time":"2024-08-12T00:00:00Z","timestamp":1723420800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:p>Cardiotoxicity and QT interval prolongation have been a common cause of withdrawal of drugs from the market. FCN-437c is an oral, second-generation, potent, and selective CDK4\/6 inhibitor for the treatment of patients with HR+\/HER2- metastatic breast cancer. A single-center, double-blind, randomized, and placebo-controlled clinical study in healthy subjects was conducted to investigate the QTc prolongation potential of FCN-437c utilizing Concentration-QTc (C-QTc) modeling approach. FCN-437c was administered at doses of 300, and 400\u00a0mg with single oral administration, along with placebo, in 18 healthy subjects. Electrocardiograms (ECGs) through 24\u00a0h holter monitor and blood samples were collected. The C<jats:sub>max<\/jats:sub> of 400\u00a0mg single dose in healthy subjects is similar to that from therapeutic dose 200\u00a0mg QD at steady state in patients with cancer. The 90% CI upper limit of \u0394\u0394QTcF at the C<jats:sub>max<\/jats:sub> geometric mean in both dose groups were &amp;lt;10\u00a0ms. It is concluded that FCN-437c has low risk of prolonging the QT interval at therapeutic dose.<\/jats:p><jats:sec><jats:title>Systematic Review Registration:<\/jats:title><jats:p><jats:ext-link>https:\/\/clinicaltrials.gov\/study\/NCT06290466?term=NCT06290466&amp;amp;rank=1<\/jats:ext-link>, identifier [NCT06290466].<\/jats:p><\/jats:sec>","DOI":"10.3389\/fphar.2024.1433663","type":"journal-article","created":{"date-parts":[[2024,8,12]],"date-time":"2024-08-12T14:40:59Z","timestamp":1723473659000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["No QTc prolongation with CDK 4\/6 inhibitor FCN-437c: results of a concentration-QTc analysis from a dedicated study in adult healthy subjects"],"prefix":"10.3389","volume":"15","author":[{"given":"Lin","family":"Zhao","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yi","family":"Sun","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaoran","family":"Yang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ling","family":"Tian","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lize","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fangfang","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaoye","family":"Niu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lei","family":"Diao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Haiyan","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2024,8,12]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"34","DOI":"10.1002\/jps.23359","article-title":"The role of BCS (biopharmaceutics classification system) and BDDCS (biopharmaceutics drug disposition classification system) in drug development","volume":"102","author":"Benet","year":"2013","journal-title":"J. Pharm. Sci."},{"key":"B2","doi-asserted-by":"publisher","first-page":"1106","DOI":"10.1002\/jcph.1844","article-title":"QT prolongation risk assessment in oncology: lessons learned from small-molecule new drug applications approved during 2011-2019","volume":"61","author":"Cohen-Rabbie","year":"2021","journal-title":"J. Clin. Pharmacol."},{"key":"B3","doi-asserted-by":"publisher","first-page":"368","DOI":"10.1111\/anec.12227","article-title":"Detection of QTc effects in small studies\u2014implications for replacing the thorough QT study","volume":"20","author":"Ferber","year":"2015","journal-title":"Ann. Noninvasive Electrocardiol."},{"key":"B4","doi-asserted-by":"publisher","first-page":"85","DOI":"10.1002\/jcph.779","article-title":"Can bias evaluation provide protection against false-negative results in QT studies without a positive control using exposure-response analysis?","volume":"57","author":"Ferber","year":"2017","journal-title":"J. Clin. Pharmacol."},{"key":"B5","doi-asserted-by":"publisher","first-page":"439","DOI":"10.1038\/nrd1108","article-title":"The impact of drug-induced QT interval prolongation on drug discovery and development","volume":"2","author":"Fermini","year":"2003","journal-title":"Nat. Rev. Drug Discov."},{"key":"B6","doi-asserted-by":"publisher","first-page":"383","DOI":"10.1007\/s10928-017-9558-5","article-title":"Scientific white paper on concentration-QTc modeling","volume":"45","author":"Garnett","year":"2018","journal-title":"J. Pharmacokinet. Pharmacodynamics"},{"key":"B7","doi-asserted-by":"publisher","first-page":"5220","DOI":"10.1038\/sj.onc.1209615","article-title":"RB and cell cycle progression","volume":"25","author":"Giacinti","year":"2006","journal-title":"Oncogene"},{"key":"B8","unstructured":"E14 clinical evaluation of QT\/QTc interval prolongation and proarrhythmic potential for non-antiarrhythmic drugs"},{"key":"B9","unstructured":"S7B nonclinical evaluation of the potential for delayed ventricular repolarization (QT interval prolongation) by human Pharmaceuticals"},{"key":"B10","unstructured":"ICH E14 guideline: the clinical evaluation of QT\/QTc interval prolongation and proarrhythmic potential for non-antiarrhythmic drugs questions and answers (R3)2015"},{"key":"B11","unstructured":"E14 and S7B clinical and nonclinical evaluation of QT\/QTc interval prolongation and proarrhythmic potential-questions and answers2022"},{"key":"B12","doi-asserted-by":"publisher","first-page":"42","DOI":"10.1097\/GCO.0000000000000243","article-title":"Cyclin-dependent kinase pathways as targets for women's cancer treatment","volume":"28","author":"Konecny","year":"2016","journal-title":"Curr. Opin. Obstetrics Gynecol."},{"key":"B13","doi-asserted-by":"publisher","first-page":"417","DOI":"10.1038\/nrclinonc.2016.26","article-title":"Treating cancer with selective CDK4\/6 inhibitors","volume":"13","author":"O\u2019leary","year":"2016","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"B14","doi-asserted-by":"publisher","first-page":"203","DOI":"10.1007\/s10928-021-09737-0","article-title":"Concentration\u2013QTc analysis for single arm studies","volume":"48","author":"Orihashi","year":"2021","journal-title":"J. Pharmacokinet. Pharmacodynamics"},{"key":"B15","doi-asserted-by":"publisher","first-page":"1164","DOI":"10.2741\/1871","article-title":"Cyclins and CDKS in development and cancer: lessons from genetically modified mice","volume":"11","author":"Santamaria","year":"2006","journal-title":"Front. Biosci. a J. Virtual Libr."},{"key":"B16","doi-asserted-by":"publisher","first-page":"305","DOI":"10.1517\/14740338.7.3.305","article-title":"Challenges of characterizing proarrhythmic risk due to QTc prolongation induced by nonadjuvant anticancer agents","volume":"7","author":"Sarapa","year":"2008","journal-title":"Expert Opin. Drug Saf."},{"key":"B17","doi-asserted-by":"publisher","first-page":"353","DOI":"10.1158\/2159-8290.CD-15-0894","article-title":"Targeting CDK4 and CDK6: from discovery to therapy","volume":"6","author":"Sherr","year":"2016","journal-title":"Cancer Discov."},{"key":"B18","doi-asserted-by":"publisher","first-page":"P4","DOI":"10.1158\/1538-7445.sabcs22-p4-01-21","article-title":"Abstract P4-01-21: phase 2 study of the CDK4\/6 inhibitor FCN-437c in combination with fulvestrant or letrozole and goserelin in patients with HR+, HER2\u2013advanced breast cancer","volume":"83","author":"Shi","year":"2023","journal-title":"Cancer Res."},{"key":"B19","doi-asserted-by":"publisher","first-page":"145","DOI":"10.3892\/ol.2024.14278","article-title":"Recommendations for cyclin-dependent kinase 4\/6 inhibitor treatments in the context of co-morbidity and drug interactions (Review)","volume":"27","author":"Teomete","year":"2024","journal-title":"Oncol. Lett."},{"key":"B20","doi-asserted-by":"publisher","first-page":"1017","DOI":"10.1038\/35082500","article-title":"Specific protection against breast cancers by cyclin D1 ablation","volume":"411","author":"Yu","year":"2001","journal-title":"Nature"},{"key":"B21","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1016\/j.ccr.2005.12.012","article-title":"Requirement for CDK4 kinase function in breast cancer","volume":"9","author":"Yu","year":"2006","journal-title":"Cancer Cell"},{"key":"B22","doi-asserted-by":"publisher","first-page":"1549","DOI":"10.1007\/s10637-021-01133-2","article-title":"Phase 1a study of the CDK4\/6 inhibitor, FCN-437c, in Chinese patients with HR+\/HER2-advanced breast cancer","volume":"39","author":"Zhang","year":"2021","journal-title":"Investig. New Drugs"},{"key":"B23","doi-asserted-by":"publisher","first-page":"1339","DOI":"10.1016\/j.ajpath.2013.06.027","article-title":"Cooperation between Dmp1 loss and cyclin D1 overexpression in breast cancer","volume":"183","author":"Zhu","year":"2013","journal-title":"Am. J. Pathology"}],"container-title":["Frontiers in Pharmacology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2024.1433663\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,8,12]],"date-time":"2024-08-12T14:41:03Z","timestamp":1723473663000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2024.1433663\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,8,12]]},"references-count":23,"alternative-id":["10.3389\/fphar.2024.1433663"],"URL":"https:\/\/doi.org\/10.3389\/fphar.2024.1433663","relation":{},"ISSN":["1663-9812"],"issn-type":[{"type":"electronic","value":"1663-9812"}],"subject":[],"published":{"date-parts":[[2024,8,12]]},"article-number":"1433663"}}