{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,6,24]],"date-time":"2025-06-24T10:05:58Z","timestamp":1750759558221,"version":"3.33.0"},"reference-count":21,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2024,9,23]],"date-time":"2024-09-23T00:00:00Z","timestamp":1727049600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100016040","name":"Takeda Canada","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100016040","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Brit J Clinical Pharma"],"published-print":{"date-parts":[[2025,2]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Aim<\/jats:title><jats:p>This study aimed to examine the cardiac and overall safety and pharmacokinetic (PK) profiles of soticlestat (TAK\u2010935), an oral, first\u2010in\u2010class selective cholesterol 24\u2010hydroxylase inhibitor.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Data came from a randomised, phase 1 study of soticlestat in 33 healthy Japanese adults (NCT04461483); 24 adults in Part 1 (single\u2010dose soticlestat 200\u20101200\u2009mg or placebo) and 9 in Part 2 (soticlestat 100\u2010300\u2009mg twice daily or placebo for 21\u2009days). PK sample collection was paired with 12\u2010lead electrocardiogram data from continuous Holter recordings. The concentration\u2010QTc relationship was analysed using a linear mixed\u2010effects model. QTc prolongation safety margins were determined for two scenarios of calculated high clinical exposures: scenario 1 (NCT05064449) involved coadministration of single\u2010dose soticlestat 300\u2009mg with itraconazole or mefenamic acid and scenario 2 (NCT05098054) involved single\u2010dose soticlestat 300\u2009mg administration in participants with mild\/moderate hepatic impairment (implementing a 3\u2010fold dose reduction for moderate severity).<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Based on concentration\u2010QTc analysis, placebo\u2010corrected change\u2010from\u2010baseline QT values (90% confidence intervals), corrected for heart rate (Fridericia's method), were 0.94\u2009ms (\u22122.35, 4.23) for soticlestat and 0.63\u2009ms (\u22123.15, 4.41) for its N\u2010oxide metabolite plasma concentrations at therapeutic doses (soticlestat 300\u2009mg twice daily); safety margins were &gt;2\u2010fold for scenarios of calculated high clinical exposures. No (Part 1) and five (83.3%; Part 2) participants experienced treatment\u2010emergent adverse events (all mild).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>There was no evidence for QT prolongation with soticlestat at therapeutic doses or in two scenarios of high clinical exposures, which resulted in regulatory agencies waiving requirements of a thorough QT study. Safety\/PK findings aligned with previous soticlestat clinical studies.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bcp.16255","type":"journal-article","created":{"date-parts":[[2024,9,24]],"date-time":"2024-09-24T00:10:03Z","timestamp":1727136603000},"page":"338-352","source":"Crossref","is-referenced-by-count":1,"title":["Concentration\u2010QTc analysis of soticlestat in healthy adults: An alternative to a thorough QT study"],"prefix":"10.1111","volume":"91","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4834-5783","authenticated-orcid":false,"given":"Wei","family":"Yin","sequence":"first","affiliation":[{"name":"Takeda Pharmaceutical Company Ltd  Cambridge Massachusetts USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nobuhito","family":"Dote","sequence":"additional","affiliation":[{"name":"PRA Development Center K.K.  Osaka Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hiroyuki","family":"Fukase","sequence":"additional","affiliation":[{"name":"Clinical Research Hospital Tokyo  Tokyo Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Manami","family":"Imazaki","sequence":"additional","affiliation":[{"name":"Takeda Development Center Japan Takeda Pharmaceutical Company Ltd  Osaka Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kohei","family":"Shimizu","sequence":"additional","affiliation":[{"name":"Takeda Development Center Japan Takeda Pharmaceutical Company Ltd  Osaka Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shinichi","family":"Takeda","sequence":"additional","affiliation":[{"name":"Takeda Development Center Japan Takeda Pharmaceutical Company Ltd  Osaka Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Borje","family":"Darpo","sequence":"additional","affiliation":[{"name":"Clario  Philadelphia Pennsylvania USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hongqi","family":"Xue","sequence":"additional","affiliation":[{"name":"Clario  Philadelphia Pennsylvania USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mahnaz","family":"Asgharnejad","sequence":"additional","affiliation":[{"name":"Takeda Pharmaceutical Company Ltd  Cambridge Massachusetts USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2024,9,23]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598\u2010020\u201074036\u20106"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.96.13.7238"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1111\/bcp.14854"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1111\/bcp.15225"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.eplepsyres.2021.106646"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1111\/epi.17367"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1111\/bcp.15917"},{"volume-title":"ICH topic E14 the clinical evaluation of QT\/QTc interval prolongation and proarrhythmic potential for non\u2010antiarrhythmic drugs","year":"2005","author":"International Conference on Harmonization","key":"e_1_2_11_9_1"},{"volume-title":"ICH guideline E14\/S7B: clinical and nonclinical evaluation of QT\/QTc interval prolongation and proarrhythmic potential \u2010 questions and answers","year":"2022","author":"International Conference on Harmonization","key":"e_1_2_11_10_1"},{"volume-title":"ICH guideline E14: the clinical evaluation of QT\/QTc interval prolongation and proarrhythmic potential for nonantiarrhythmic drugs (R3) \u2010 questions and answers","year":"2016","author":"International Conference on Harmonization","key":"e_1_2_11_11_1"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1124\/dmd.123.001444"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1002\/prp2.1213"},{"volume-title":"The early precision QT approach [white paper]","year":"2018","author":"Darpo B","key":"e_1_2_11_14_1"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10928\u2010017\u20109558\u20105"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.16181"},{"key":"e_1_2_11_17_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.16176"},{"key":"e_1_2_11_18_1","doi-asserted-by":"publisher","DOI":"10.1002\/psp4.12580"},{"key":"e_1_2_11_19_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00280\u2010020\u201004204\u2010y"},{"key":"e_1_2_11_20_1","doi-asserted-by":"publisher","DOI":"10.1208\/s12248\u2010021\u201000573\u20101"},{"key":"e_1_2_11_21_1","doi-asserted-by":"publisher","DOI":"10.1111\/cts.13722"},{"key":"e_1_2_11_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.yebeh.2023.109173"}],"container-title":["British Journal of Clinical Pharmacology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/bpspubs.onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/bcp.16255","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,1,28]],"date-time":"2025-01-28T07:08:48Z","timestamp":1738048128000},"score":1,"resource":{"primary":{"URL":"https:\/\/bpspubs.onlinelibrary.wiley.com\/doi\/10.1111\/bcp.16255"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,9,23]]},"references-count":21,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2025,2]]}},"alternative-id":["10.1111\/bcp.16255"],"URL":"https:\/\/doi.org\/10.1111\/bcp.16255","archive":["Portico"],"relation":{},"ISSN":["0306-5251","1365-2125"],"issn-type":[{"type":"print","value":"0306-5251"},{"type":"electronic","value":"1365-2125"}],"subject":[],"published":{"date-parts":[[2024,9,23]]}}}