{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,7,27]],"date-time":"2025-07-27T07:48:17Z","timestamp":1753602497324,"version":"3.37.0"},"reference-count":21,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2024,11,5]],"date-time":"2024-11-05T00:00:00Z","timestamp":1730764800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100004325","name":"AstraZeneca","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100004325","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["CPT Pharmacom &amp; Syst Pharma"],"published-print":{"date-parts":[[2025,2]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Balcinrenone (AZD9977) is a selective mineralocorticoid receptor modulator in development in combination with dapagliflozin for treatment of heart failure with impaired kidney function and chronic kidney disease. A prespecified concentration\u2013QT analysis was performed based on data from a phase I single ascending dose study prospectively designed as a thorough QT study substitute. Oral single doses of balcinrenone of 5\u2013800\u2009mg, plus fractionated doses of 800 and 1200\u2009mg, were evaluated in 62 healthy male participants. Time\u2010matched 12\u2010lead digital electrocardiogram and plasma concentrations were measured pre\u2010dose and up to 48\u2009h postdose in the participants. Analysis was performed using a linear mixed\u2010effect model, where baseline\u2010adjusted Fridericia\u2010corrected QT interval (\u0394QTcF) was a dependent variable and time\u2010matched balcinrenone concentration an independent variable. The model fit was deemed adequate by evaluation of goodness\u2010of\u2010fit plots, and the slope of the concentration\u2013\u0394QTcF relationship was nonsignificant (\u22120.003\u2009ms\/\u03bcmol\/L; 95% confidence interval [CI]: \u22120.181, 0.176). The high clinical exposure scenario was defined as the maximum concentration (2.156\u2009\u03bcmol\/L) following the highest expected therapeutic dose (40\u2009mg once daily) under fed conditions and in presence of a strong cytochrome P450\u00a03A4 inhibitor. Estimated baseline\u2010adjusted and placebo\u2010corrected QTcF interval (\u0394\u0394QTcF) at this concentration was 0.35\u2009ms (90% CI: \u22121.29, 2.00). Furthermore, the upper 90% \u0394\u0394QTcF CI was estimated to be below the threshold of regulatory concern of 10\u2009ms at all observed concentrations (up to 16.7\u2009\u03bcmol\/L). Hence, it can be concluded that balcinrenone does not induce QTcF prolongation at the high clinical exposure scenario.<\/jats:p>","DOI":"10.1002\/psp4.13272","type":"journal-article","created":{"date-parts":[[2024,11,5]],"date-time":"2024-11-05T08:43:54Z","timestamp":1730796234000},"page":"292-301","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Concentration\u2013QT modeling demonstrates that the selective mineralocorticoid receptor modulator, balcinrenone (AZD9977), does not prolong QT interval"],"prefix":"10.1002","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5395-9819","authenticated-orcid":false,"given":"Jesper","family":"Sundell","sequence":"first","affiliation":[{"name":"Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and Safety Sciences, BioPharmaceuticals R&amp;D AstraZeneca  Gothenburg Sweden"},{"name":"Lund University  Lund Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5310-8002","authenticated-orcid":false,"given":"Dinko","family":"Rekic","sequence":"additional","affiliation":[{"name":"Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and Safety Sciences, BioPharmaceuticals R&amp;D AstraZeneca  Gothenburg Sweden"},{"name":"Alexion AstraZeneca, Rare Disease  Boston Massachusetts USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5463-8398","authenticated-orcid":false,"given":"Johanna","family":"Melin","sequence":"additional","affiliation":[{"name":"Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and Safety Sciences, BioPharmaceuticals R&amp;D AstraZeneca  Gothenburg Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5643-0278","authenticated-orcid":false,"given":"Susanne","family":"Johansson","sequence":"additional","affiliation":[{"name":"Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and Safety Sciences, BioPharmaceuticals R&amp;D AstraZeneca  Gothenburg Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4401-9729","authenticated-orcid":false,"given":"Ahmad","family":"Ebrahimi","sequence":"additional","affiliation":[{"name":"Cardiovascular Safety Center of Excellence and SKGs, Global Patient Safety, Oncology R&amp;D AstraZeneca  Gothenburg Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Corina","family":"Dota","sequence":"additional","affiliation":[{"name":"Cardiovascular Safety Center of Excellence and SKGs, Global Patient Safety, Oncology R&amp;D AstraZeneca  Gothenburg Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4492-5243","authenticated-orcid":false,"given":"Joanna","family":"Parkinson","sequence":"additional","affiliation":[{"name":"Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and Safety Sciences, BioPharmaceuticals R&amp;D AstraZeneca  Gothenburg Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2024,11,5]]},"reference":[{"key":"e_1_2_12_2_1","doi-asserted-by":"publisher","DOI":"10.1097\/med.0b013e3283391989"},{"key":"e_1_2_12_3_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2017.00313"},{"key":"e_1_2_12_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/ki.2011.48"},{"key":"e_1_2_12_5_1","doi-asserted-by":"publisher","DOI":"10.1161\/HYPERTENSIONAHA.114.04488"},{"key":"e_1_2_12_6_1","doi-asserted-by":"publisher","DOI":"10.1111\/cts.13377"},{"key":"e_1_2_12_7_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0193380"},{"key":"e_1_2_12_8_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1476-5381.2009.00487.x"},{"key":"e_1_2_12_9_1","unstructured":"US Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) Center for Biologics Evaluation and Research (CBER).E14 clinical evaluation of QT\/QTc interval prolongation and proarrhythmic potential for non\u2010antiarrhythmic drugs. Guidance for industry.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 August 15 2024."},{"key":"e_1_2_12_10_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10928-017-9558-5"},{"key":"e_1_2_12_11_1","unstructured":"US Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) Center for Biologics Evaluation and Research (CBER).E14 clinical evaluation of QT\/QTc interval prolongation and proarrhythmic potential for non\u2010antiarrhythmic drugs \u2014 Questions and answers (R3). Guidance for industry.2017.https:\/\/www.fda.gov\/media\/71379\/download. Accessed August 15 2024."},{"key":"e_1_2_12_12_1","doi-asserted-by":"publisher","DOI":"10.1177\/0091270007307881"},{"key":"e_1_2_12_13_1","doi-asserted-by":"publisher","DOI":"10.1111\/bcp.15425"},{"key":"e_1_2_12_14_1","doi-asserted-by":"publisher","DOI":"10.1111\/bcp.15006"},{"key":"e_1_2_12_15_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.60"},{"key":"e_1_2_12_16_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpdd.605"},{"key":"e_1_2_12_17_1","doi-asserted-by":"publisher","DOI":"10.1111\/cts.12779"},{"key":"e_1_2_12_18_1","doi-asserted-by":"publisher","DOI":"10.1111\/bcp.13562"},{"key":"e_1_2_12_19_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.0954-6820.1920.tb18266.x"},{"key":"e_1_2_12_20_1","unstructured":"US Food and Drug Administration.E14 and S7B clinical and nonclinical evaluation of QT\/QTc interval prolongation and proarrhythmic potential \u2014 Questions and answers. Guidance for industry.2022.https:\/\/www.fda.gov\/media\/161198\/download. 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