{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T04:17:19Z","timestamp":1792556239922,"version":"4.5.0"},"reference-count":21,"publisher":"Wiley","issue":"11","license":[{"start":{"date-parts":[[2022,6,10]],"date-time":"2022-06-10T00:00:00Z","timestamp":1654819200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Brit J Clinical Pharma"],"published-print":{"date-parts":[[2022,11]]},"abstract":"<jats:sec><jats:title>Aims<\/jats:title><jats:p>AZD8233 is a proprotein convertase subtilisin\/kexin type 9 (PCSK9) antisense oligonucleotide under development for treatment of hypercholesterolaemia. A prespecified concentration\u2010QT analysis was performed based on data from a single ascending dose study that was prospectively designed to act as a TQT study substitute.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Subcutaneous single doses ranging from 4 to 120\u2009mg were evaluated in 73 adult healthy male subjects. Time\u2010matched 12\u2010lead digital ECG and plasma concentrations (<jats:italic>n<\/jats:italic>\u2009=\u200915) were measured at baseline and up to 48\u2009hours after dose in each subject. The analysis was performed using a linear mixed effect model, where change from baseline QTc (\u0394QTc) was a dependent variable and time\u2010matched AZD8233 concentration was an independent variable.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The high clinical exposure scenario was defined as 1.7\u2010fold the expected <jats:italic>C<\/jats:italic><jats:sub>max<\/jats:sub> following an assumed therapeutic dose of 60\u2009mg, which corresponds to AZD8233 plasma concentration of 1.39\u2009\u03bcg\/mL. Estimated placebo\u2010corrected and baseline\u2010adjusted QTcF interval (\u0394\u0394QTcF) at this concentration was \u22122.2\u00a0ms (90% CI: \u22124.11, \u22120.28). Furthermore, the upper 90% \u0394\u0394QTcF confidence interval was estimated to be below 10\u00a0ms at all observed concentrations.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>As the effect on \u0394\u0394QTcF is below the threshold for regulatory concern (10\u00a0ms), it can be concluded that AZD8233 does not induce QTcF prolongation at the high clinical exposure scenario.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bcp.15425","type":"journal-article","created":{"date-parts":[[2022,6,2]],"date-time":"2022-06-02T16:30:20Z","timestamp":1654187420000},"page":"4839-4844","source":"Crossref","is-referenced-by-count":16,"title":["AZD8233 antisense oligonucleotide targeting PCSK9 does not prolong QT interval"],"prefix":"10.1111","volume":"88","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5310-8002","authenticated-orcid":false,"given":"Dinko","family":"Reki\u0107","sequence":"first","affiliation":[{"name":"Clinical Pharmacology and Quantitative Pharmacology, 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Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ahmad","family":"Ebrahimi","sequence":"additional","affiliation":[{"name":"Cardiovascular Safety Center of Excellence Global Patient Safety, Oncology R&amp;D  Gothenburg AZ Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Corina","family":"Dota","sequence":"additional","affiliation":[{"name":"Cardiovascular Safety Center of Excellence Global Patient Safety, Oncology R&amp;D  Gothenburg AZ Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bj\u00f6rn","family":"Carlsson","sequence":"additional","affiliation":[{"name":"Research and Early Development, Cardiovascular, Renal, and Metabolism BioPharmaceuticals R&amp;D, AstraZeneca  Gothenburg 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