{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T02:19:34Z","timestamp":1768443574103,"version":"3.49.0"},"reference-count":24,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2023,7,4]],"date-time":"2023-07-04T00:00:00Z","timestamp":1688428800000},"content-version":"vor","delay-in-days":0,"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":[[2023,9]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Abemaciclib is an orally administered, potent, and selective small molecule inhibitor of cyclin\u2010dependent kinases 4 and 6, approved for advanced or metastatic breast cancer. This study aimed to use an exposure\u2013response approach to investigate the effect of abemaciclib and its active metabolites (M2 and M20) on QTc interval and delay in cardiac repolarization at clinically relevant exposures. This was a single\u2010blind, randomized, and placebo\u2010controlled study of ascending doses of abemaciclib. Thirty\u2010five healthy participants were administered a single dose of 200\u2013600\u2009mg abemaciclib. Twelve\u2010lead electrocardiogram tracings and pharmacokinetic samples were collected serially pre\u2010 and post\u2010dose. The primary objective was to study the relationship between abemaciclib and its active metabolites (M2 and M20) and QTc interval following ascending oral doses of abemaciclib. The secondary objective included evaluating the safety and tolerability of single ascending doses of abemaciclib in healthy participants. Exposure\u2013response analysis demonstrated that there was no significant relationship between placebo\u2010corrected change from baseline QTcF (\u0394\u0394QTcF), abemaciclib, and metabolite plasma concentrations. Additionally, the \u0394\u0394QTcF slopes of abemaciclib, its metabolites, and total analyte concentrations were not statistically different from zero. Single doses of abemaciclib, up to 400\u2009mg, were well\u2010tolerated by healthy participants; however, at the 600\u2009mg dose (three times the highest registered dose), the frequency and severity of treatment\u2010related gastrointestinal events (primarily diarrhea, nausea, and vomiting) increased. In conclusion, single doses of abemaciclib, up to 400\u2009mg, had no statistically or clinically relevant effects on QTc, and abemaciclib was well tolerated up to a dose of 400\u2009mg in this study.<\/jats:p>","DOI":"10.1111\/cts.13573","type":"journal-article","created":{"date-parts":[[2023,6,20]],"date-time":"2023-06-20T06:22:38Z","timestamp":1687242158000},"page":"1617-1627","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Abemaciclib does not increase the corrected <scp>QT<\/scp> interval in healthy participants"],"prefix":"10.1111","volume":"16","author":[{"given":"Jill C.","family":"Chappell","sequence":"first","affiliation":[{"name":"Eli Lilly and Company  Indianapolis Indiana USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alan Y.","family":"Chiang","sequence":"additional","affiliation":[{"name":"Eli Lilly and Company  Indianapolis Indiana USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jane","family":"Royalty","sequence":"additional","affiliation":[{"name":"Covance Early Clinical Development  Madison Wisconsin USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hugh","family":"Coleman","sequence":"additional","affiliation":[{"name":"Covance Clinical Research Unit  Daytona Beach Florida USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Palaniappan","family":"Kulanthaivel","sequence":"additional","affiliation":[{"name":"Eli Lilly and Company  Indianapolis Indiana USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8703-5438","authenticated-orcid":false,"given":"P. Kellie","family":"Turner","sequence":"additional","affiliation":[{"name":"Eli Lilly and Company  Indianapolis Indiana USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2023,7,4]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10637-014-0120-7"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.60"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1111\/anec.12128"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40264-015-0325-5"},{"key":"e_1_2_10_6_1","unstructured":"International Conference on Harmonisation (ICH).Final concept paper: E14 Q&As (R3): revision of ICH E14 Q&As (R2). 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