{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,24]],"date-time":"2026-03-24T14:33:12Z","timestamp":1774362792061,"version":"3.50.1"},"reference-count":34,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2026,3,22]],"date-time":"2026-03-22T00:00:00Z","timestamp":1774137600000},"content-version":"vor","delay-in-days":21,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,3,1]],"date-time":"2026-03-01T00:00:00Z","timestamp":1772323200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["accp1.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clinical Pharm in Drug Dev"],"published-print":{"date-parts":[[2026,3]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Givinostat is a class I\/II histone deacetylase inhibitor indicated for Duchenne muscular dystrophy (DMD). The study evaluated the effect of therapeutic and supratherapeutic givinostat doses on the QT\/QTc interval. Healthy volunteers received each treatment\u2014givinostat hydrochloride monohydrate oral suspension as a therapeutic (100\u00a0mg) or supratherapeutic (300\u00a0mg) dose, placebo oral suspension, or moxifloxacin oral tablet (positive control, 400\u00a0mg)\u2014according to a block randomization scheme. Cardiodynamic assessments were paired with pharmacokinetic samples. A small, clinically non\u2010relevant effect on mean placebo\u2010corrected, change\u2010from\u2010baseline QTcF (\u2206\u2206QTcF) of 5.5\u00a0ms was seen after givinostat 100\u2010mg dose. Clinically relevant QTc prolongation was observed with the supratherapeutic dose, with a mild \u2206\u2206QTcF increase of 13.6\u00a0ms. A delay of \u22483\u00a0h between T\n                    <jats:sub>max<\/jats:sub>\n                    and the largest effect on the QTc interval was seen for both doses. In the concentration\u2010QTc analysis, an E\n                    <jats:sub>max<\/jats:sub>\n                    model captured the data better than the prespecified linear model and showed that an effect on \u2206\u2206QTcF exceeding 10\u00a0ms could be excluded within the full range of observed givinostat concentrations in this study and up to \u2248745\u00a0ng\/mL. Givinostat at the maximum labeled dose (up to 53.2\u00a0mg twice daily for DMD) is not expected to pose a QT prolongation risk.\n                  <\/jats:p>","DOI":"10.1002\/cpdd.70047","type":"journal-article","created":{"date-parts":[[2026,3,23]],"date-time":"2026-03-23T04:15:54Z","timestamp":1774239354000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Thorough QT Study on the Effect of Therapeutic and Supratherapeutic Dosing of Givinostat in Healthy Volunteers"],"prefix":"10.1002","volume":"15","author":[{"given":"Eugenio","family":"Mercuri","sequence":"first","affiliation":[{"name":"Pediatric Neurology Institute Catholic University and Nemo Pediatrico \u00a0Fondazione Policlinico Gemelli IRCCS  Rome Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Barry","family":"Byrne","sequence":"additional","affiliation":[{"name":"Institute for Child Health Policy University of Florida  Gainesville Florida USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tracey","family":"Willis","sequence":"additional","affiliation":[{"name":"The Robert Jones and Agnes Hunt Orthopaedic Hospital NHS Foundation Trust  Oswestry UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"John","family":"Bourke","sequence":"additional","affiliation":[{"name":"The John Walton Muscular Dystrophy Research Centre, Freeman Hospital Newcastle University and Newcastle Hospitals NHS Foundation Trust  Newcastle upon Tyne UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Paolo","family":"Bettica","sequence":"additional","affiliation":[{"name":"Italfarmaco S.p.A.  Milan Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sara","family":"Cazzaniga","sequence":"additional","affiliation":[{"name":"Italfarmaco S.p.A.  Milan Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hongqi","family":"Xue","sequence":"additional","affiliation":[{"name":"Clario, Philadelphia  Pennsylvania USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Borje","family":"Darpo","sequence":"additional","affiliation":[{"name":"Clario, Philadelphia  Pennsylvania USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2026,3,22]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.2119\/molmed.2013.00011"},{"key":"e_1_2_10_3_1","unstructured":"Italfarmaco S.p.A. Duvyzat (givinostat) prescribing information. Italfarmaco S.p.A.; 2024."},{"key":"e_1_2_10_4_1","unstructured":"FDA approves nonsteroidal treatment for Duchenne muscular dystrophy.US Food and Drug Administration. March 21 2024. Accessed February 7 2025.https:\/\/www.fda.gov\/news\u2010events\/press\u2010announcements\/fda\u2010approves\u2010nonsteroidal\u2010treatment\u2010duchenne\u2010muscular\u2010dystrophy."},{"key":"e_1_2_10_5_1","unstructured":"Givinostat conditionally approved to treat patients with Duchenne muscular dystrophy (DMD).Medicines and Healthcare Products Regulatory Agency. November 7 2024. Accessed January 29 2025.https:\/\/www.gov.uk\/government\/news\/givinostat\u2010conditionally\u2010approved\u2010to\u2010treat\u2010patients\u2010with\u2010duchenne\u2010muscular\u2010dystrophy\u2010dmd."},{"key":"e_1_2_10_6_1","unstructured":"New treatment against Duchenne muscular dystrophy.European Medicines Agency. June 20 2025. Accessed June 23 2025.https:\/\/www.ema.europa.eu\/en\/news\/new\u2010treatment\u2010against\u2010duchenne\u2010muscular\u2010dystrophy."},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(24)00036-X"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41408-021-00445-z"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.30238"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.3389\/fneur.2023.1095121"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40264-018-0773-9"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijcard.2016.06.012"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2024.1514898"},{"key":"e_1_2_10_14_1","unstructured":"Guidance for industry: E14 clinical evaluation of QT\/QTc interval prolongation and proarrhythmic potential for non\u2010antiarrhythmic drugs.US Food and Drug Administration. October 2005. Accessed April 1 2025.https:\/\/www.fda.gov\/media\/71372\/download."},{"key":"e_1_2_10_15_1","unstructured":"ICH E14: the clinical evaluation of QT\/QTc interval prolongation and proarrhythmic potential for non\u2010antiarrhythmic drugs.European Medicines Agency. May 2005. Accessed February 19 2025.https:\/\/www.ema.europa.eu\/en\/ich\u2010e14\u2010clinical\u2010evaluation\u2010qt\u2010qtc\u2010interval\u2010prolongation\u2010proarrhythmic\u2010potential\u2010non\u2010antiarrhythmic\u2010drugs\u2010scientific\u2010guideline."},{"key":"e_1_2_10_16_1","unstructured":"ICH E14 guideline: the clinical evaluation of QT\/QTc interval prolongation and proarrhythmic potential for non\u2010antiarrhythmic drugs.European Medicines Agency. December 2015. Accessed June 4 2025.https:\/\/database.ich.org\/sites\/default\/files\/E14_Q%26As_R3_Q%26As.pdf."},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.bjp.0706389"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1002\/acn3.70165"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nmd.2016.07.002"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.2119\/molmed.2011.00020"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41375-020-0735-y"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.1080\/17425255.2023.2219839"},{"key":"e_1_2_10_23_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_10_24_1","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.02385-16"},{"key":"e_1_2_10_25_1","doi-asserted-by":"publisher","DOI":"10.1080\/10543400903581945"},{"key":"e_1_2_10_26_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.60"},{"key":"e_1_2_10_27_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10928-017-9558-5"},{"key":"e_1_2_10_28_1","doi-asserted-by":"publisher","DOI":"10.18433\/J3GP53"},{"key":"e_1_2_10_29_1","volume-title":"Cardiac safety data for givinostat in ambulant patients with Duchenne muscular dystrophy: results from EPIDYS study","author":"Mercuri E","year":"2025"},{"key":"e_1_2_10_30_1","unstructured":"MercuriE BellantiF CazzanigaS BetticaP McDonaldCM.A simplified givinostat dosing regimen minimizes exposure differences and dose reductions in higher\u2010weight patients. Paper presented at:American Association of Neuromuscular & Electrodiagnostic Medicine Annual Meeting; October 29\u2013November 1 2025;San Francisco California."},{"key":"e_1_2_10_31_1","doi-asserted-by":"publisher","DOI":"10.1186\/s40164-024-00507-5"},{"key":"e_1_2_10_32_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.semcancer.2025.05.008"},{"key":"e_1_2_10_33_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(22)00221-2"},{"key":"e_1_2_10_34_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41569-020-0348-1"},{"key":"e_1_2_10_35_1","doi-asserted-by":"publisher","DOI":"10.5966\/sctm.2015-0279"}],"container-title":["Clinical Pharmacology in Drug Development"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/accp1.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cpdd.70047","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/accp1.onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/cpdd.70047","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/accp1.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cpdd.70047","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,24]],"date-time":"2026-03-24T13:48:13Z","timestamp":1774360093000},"score":1,"resource":{"primary":{"URL":"https:\/\/accp1.onlinelibrary.wiley.com\/doi\/10.1002\/cpdd.70047"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3]]},"references-count":34,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2026,3]]}},"alternative-id":["10.1002\/cpdd.70047"],"URL":"https:\/\/doi.org\/10.1002\/cpdd.70047","archive":["Portico"],"relation":{},"ISSN":["2160-763X","2160-7648"],"issn-type":[{"value":"2160-763X","type":"print"},{"value":"2160-7648","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,3]]},"assertion":[{"value":"2025-11-24","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-02-18","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-03-22","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70047"}}