{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T20:20:51Z","timestamp":1790194851987,"version":"4.1.0"},"reference-count":41,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2024,5,6]],"date-time":"2024-05-06T00:00:00Z","timestamp":1714953600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clin Pharma and Therapeutics"],"published-print":{"date-parts":[[2024,7]]},"abstract":"<jats:p>The ICH E14\/S7B Q&amp;As highlighted the need for best practices concerning the design, execution, analysis, interpretation, and reporting of the <jats:italic>in vivo<\/jats:italic> non\u2010rodent QT assay as a component of the integrated risk assessment to potentially support a TQT waiver or substitute. We conducted a dog telemetry study to assess the effects on QTc of six reference compounds (five positive and one negative) previously evaluated by Darpo <jats:italic>et al.<\/jats:italic> (2015) in humans. The sensitivity of the assay to detect QTc increases was determined, and exposure\u2013response analysis was performed, as done in clinical practice. By\u2010timepoint analysis showed QTc prolongation induced by moxifloxacin, dofetilide, dolasetron, ondansetron, and quinine within human relevant plasma exposures ranges. Moreover, a hysteresis was observed for quinine. As expected, levocetirizine showed no statistically significant effect on QTc across a range of exposure, well exceeding the therapeutic <jats:italic>C<\/jats:italic><jats:sub>max<\/jats:sub>. Power analyses confirmed the study ability to detect statistically significant QTc changes of less than 10\u2009milliseconds with 80% probability, even with a sample size as low as <jats:italic>n<\/jats:italic>\u2009=\u20094 animals. Finally, concentration\u2010QTc modeling enabled to predict the minimal plasma concentration needed to detect a 10\u2009milliseconds QTc prolongation, including for quinine. The comparison with clinical available data supported the relevance of dogs under these experimental conditions as a robust translational predictor of drug\u2010induced QTc prolongation in humans as a key pillar of the integrated risk assessment.<\/jats:p>","DOI":"10.1002\/cpt.3283","type":"journal-article","created":{"date-parts":[[2024,5,6]],"date-time":"2024-05-06T14:38:43Z","timestamp":1715006323000},"page":"106-116","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Results from a Joined Prospective Study to Evaluate the Sensitivity of the <i>In Vivo<\/i> Dog <scp>QT<\/scp> Assay in Line with the <scp>ICH E14<\/scp>\/<scp>S7B<\/scp> Q&amp;A Best Practices"],"prefix":"10.1002","volume":"116","author":[{"given":"Anne\u2010Marie","family":"B\u00e9tat","sequence":"first","affiliation":[{"name":"Non\u2010Clinical Department Biotrial Pharmacology  Rennes France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6345-7989","authenticated-orcid":false,"given":"Annie","family":"Delaunois","sequence":"additional","affiliation":[{"name":"Early Clinical Development &amp; Translational Science Department UCB Biopharma SRL  Braine\u2010l'Alleud Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8056-3652","authenticated-orcid":false,"given":"Eric","family":"Delpy","sequence":"additional","affiliation":[{"name":"Non\u2010Clinical Department Biotrial Pharmacology  Rennes France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mathilde","family":"Loiseau","sequence":"additional","affiliation":[{"name":"Non\u2010Clinical Department Biotrial Pharmacology  Rennes France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne","family":"Maurin","sequence":"additional","affiliation":[{"name":"Non\u2010Clinical Department Biotrial Pharmacology  Rennes France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gwendoline","family":"Poizat","sequence":"additional","affiliation":[{"name":"Biostatistics Department Biotrial  Rennes France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Celine","family":"Poss\u00e9m\u00e9","sequence":"additional","affiliation":[{"name":"Non\u2010Clinical Department Biotrial Pharmacology  Rennes France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ferdinand","family":"Weinelt","sequence":"additional","affiliation":[{"name":"Department of Drug Discovery Sciences\u2010PKPD Modeling Boehringer Ingelheim Pharma  Biberach\/Riss Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christophe","family":"Drieu la Rochelle","sequence":"additional","affiliation":[{"name":"Non\u2010Clinical Department Biotrial Pharmacology  Rennes France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8015-7283","authenticated-orcid":false,"given":"Eric","family":"Martel","sequence":"additional","affiliation":[{"name":"Department of Drug Discovery Sciences\u2010General Pharmacology Boehringer Ingelheim Pharma  Biberach\/Riss Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean\u2010Pierre","family":"Valentin","sequence":"additional","affiliation":[{"name":"Early Clinical Development &amp; Translational Science Department UCB Biopharma SRL  Braine\u2010l'Alleud Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2024,5,6]]},"reference":[{"key":"e_1_2_10_1_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.60"},{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1177\/107424840200700202"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/1047-2797(94)00039-V"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrd.2015.34"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.2137"},{"key":"e_1_2_10_6_1","unstructured":"Anonymous.ICH S7B: the nonclinical evaluation of the potential for delayed ventricular repolarization (QT interval prolongation) by human pharmaceuticalsCPMP\/ICH\/423\/02 <http:\/\/www.emea.eu.int\/pdfs\/human\/ich\/042302en.pdf> (2005) Accessed November 2023."},{"key":"e_1_2_10_7_1","unstructured":"Anonymous.ICH E14: the clinical evaluation of QT\/QTc interval prolongation and proarrhythmic potential for non\u2010antiarrhythmic drugs. CPMP\/ICH\/2\/04<http:\/\/www.emea.eu.int\/pdfs\/human\/ich\/000204en.pdf> (2005) Accessed November 2023."},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1111\/bcp.12082"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1111\/bcp.13123"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1093\/toxsci\/kfu198"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.vascn.2014.12.008"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.vascn.2013.05.004"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.vascn.2013.03.007"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1093\/toxsci\/kfx125"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1476-5381.2009.00395.x"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.vascn.2011.03.002"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.13207"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.14101"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1093\/toxsci\/kfac013"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.vascn.2023.107265"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.vascn.2023.107270"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.2029"},{"key":"e_1_2_10_23_1","unstructured":"Anonymous.ICH E14\/S7B Q&As. 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