{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,20]],"date-time":"2026-01-20T03:38:44Z","timestamp":1768880324333,"version":"3.49.0"},"reference-count":14,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2024,1,29]],"date-time":"2024-01-29T00:00:00Z","timestamp":1706486400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["accp1.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clinical Pharm in Drug Dev"],"published-print":{"date-parts":[[2024,5]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Icenticaftor (QBW251) is a potentiator of the cystic fibrosis transmembrane receptor. Based on its mechanism of action, icenticaftor is expected to provide benefits in patients with chronic obstructive pulmonary disease by restoring mucociliary clearance, which would eventually lead to a reduction of bacterial colonization and related inflammatory cascade. A placebo\u2010 and positive\u2010controlled, 4\u2010way crossover thorough QT study was conducted in 46 healthy participants with the objective to assess the effect of therapeutic (300\u00a0mg twice daily for 6 days) and supratherapeutic (750\u00a0mg twice daily for 6 days) oral doses of icenticaftor on electrocardiogram parameters, including concentration\u2010corrected QT (QTc) analysis. Moxifloxacin (400\u00a0mg, oral) was used as a positive control. In the concentration\u2010QTc analysis performed on pooled data from Day 1 and Day 6 (steady state), the estimated population slope was shallow and slightly negative: \u20130.0012\u00a0ms\/ng\/mL. The effect on the Fridericia corrected QT (QTcF) interval (\u2206\u0394QTcF) was predicted to be \u22121.3\u00a0milliseconds at the icenticaftor 300\u2010mg twice\u2010daily peak concentration (geometric mean was 1094\u00a0ng\/mL) and \u22125.5\u00a0milliseconds at the 750\u2010mg twice\u2010daily peak concentration (geometric mean C<jats:sub>max<\/jats:sub> was 4529\u00a0ng\/mL) indicated a mild shortening effect of icenticaftor on QTcF interval length. The results of the by\u2010time\u2010point analysis indicated least squares placebo corrected mean \u2206\u2206QTcF across time points ranged from \u20137.9 to 0.1\u00a0milliseconds at 1 and 24\u00a0hours after dosing both on Day 6 in the 750\u2010mg dose group compared with \u20133.7 to 1.6\u00a0milliseconds at 1.5 and 24 hours after dosing on Day\u00a01 in the 300\u2010mg dose group. Assay sensitivity was demonstrated with moxifloxacin. The large accumulation of exposures, especially the 4.3\u2010fold increase in peak plasma concentration observed at the icenticaftor 750\u2010mg twice\u2010daily dosage compared with Icenticaftor 300\u00a0mg twice daily (2.3\u2010fold) on Day 6 provided a large concentration range (up to 9540\u00a0ng\/mL) to evaluate the effect of icenticaftor on \u0394\u0394QTcF. Based on the concentration\u2013QTc analysis, an effect on \u0394\u0394QTcF exceeding 10\u00a0milliseconds can be excluded within the full observed ranges of plasma concentrations on icenticaftor, up to approximately 9540\u00a0ng\/mL. Icenticaftor at the studied doses demonstrated a mild shortening in QTcF, which is unlikely to be of clinical relevance in a therapeutic setting.<\/jats:p>","DOI":"10.1002\/cpdd.1374","type":"journal-article","created":{"date-parts":[[2024,1,29]],"date-time":"2024-01-29T11:14:57Z","timestamp":1706526897000},"page":"572-584","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Concentration\u2010QTcF Modeling of Icenticaftor from a Randomized, Placebo\u2010 and Positive\u2010Controlled Thorough QT Study in Healthy Participants"],"prefix":"10.1002","volume":"13","author":[{"given":"Ganesh R.","family":"Iyer","sequence":"first","affiliation":[{"name":"Biomedical Research Novartis Pharmaceuticals Corporation  Cambridge MA USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Borje","family":"Darpo","sequence":"additional","affiliation":[{"name":"Clario  Philadelphia USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hongqi","family":"Xue","sequence":"additional","affiliation":[{"name":"Clario  Philadelphia USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jean","family":"Lecot","sequence":"additional","affiliation":[{"name":"Biomedical Research Novartis Pharma AG  Basel Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Julia","family":"Zack","sequence":"additional","affiliation":[{"name":"Biomedical Research Novartis Pharmaceuticals Corporation  East Hanover NJ USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lidiya","family":"Bebrevska","sequence":"additional","affiliation":[{"name":"Biomedical Research Novartis Pharma AG  Basel Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wendy","family":"Weis","sequence":"additional","affiliation":[{"name":"Biomedical Research Novartis Pharmaceuticals Corporation  East Hanover NJ USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ieuan","family":"Jones","sequence":"additional","affiliation":[{"name":"Biomedical Research Novartis Pharma AG  Basel Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anton","family":"Drollmann","sequence":"additional","affiliation":[{"name":"Biomedical Research Novartis Pharma AG  Basel Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2024,1,29]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa032158"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1080\/15412550802522445"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1164\/ajrccm.161.3.9907080"},{"issue":"1437","key":"e_1_2_8_5_1","first-page":"1","article-title":"Dysfunction in the cystic fibrosis transmembrane regulator in chronic obstructive pulmonary disease as a potential target for personalized medicine","volume":"9","author":"Carrasco\u2010Hern\u00e1ndez L","year":"2021","journal-title":"Biomedicines"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jcf.2020.11.002"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.2147\/COPD.S257474"},{"key":"e_1_2_8_8_1","first-page":"41","article-title":"Icenticaftor, a CFTR potentiator, in COPD. A multicenter, parallel\u2010group, double\u2010blind clinical trial","volume":"4","author":"Martinez FJ","year":"2023","journal-title":"Am J Respir Crit Care Med"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpdd.653"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.1c00343"},{"issue":"4","key":"e_1_2_8_11_1","first-page":"401","article-title":"Improving the precision of QT measurements","volume":"18","author":"Darpo B","year":"2011","journal-title":"Cardiol J"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10928-017-9558-5"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1080\/10543400802020938"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ahj.2014.06.003"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcph.2309"}],"container-title":["Clinical Pharmacology in Drug Development"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/accp1.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cpdd.1374","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,4,24]],"date-time":"2024-04-24T07:59:57Z","timestamp":1713945597000},"score":1,"resource":{"primary":{"URL":"https:\/\/accp1.onlinelibrary.wiley.com\/doi\/10.1002\/cpdd.1374"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,1,29]]},"references-count":14,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2024,5]]}},"alternative-id":["10.1002\/cpdd.1374"],"URL":"https:\/\/doi.org\/10.1002\/cpdd.1374","archive":["Portico"],"relation":{},"ISSN":["2160-763X","2160-7648"],"issn-type":[{"value":"2160-763X","type":"print"},{"value":"2160-7648","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,1,29]]},"assertion":[{"value":"2023-10-17","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-12-19","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-01-29","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}