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The first lead compounds tested in anesthetized guinea pigs (GPs) induced profound QRS widening, although exhibiting weak inhibition of NaV1.5-mediated currents in standard patch clamp assays. To understand the mechanism(s) underlying QRS widening to identify further compounds devoid of such liability, we established a set of in vitro models including CaV1.2, NaV1.5 rate-dependence, and NaV1.8 patch clamp assays, human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM), and Langendorff-perfused isolated GP hearts. Six compounds were tested in all models including anesthetized GP, and 8 additional compounds were tested in vitro only. All compounds tested in anesthetized GP and isolated hearts showed a similar cardiovascular profile, consisting of QRS widening, bradycardia, negative inotropy, hypotension, and for some, QT prolongation. However, a left shift of the concentration\u2013response curves was noted from in vitro to in vivo GP data. When comparing in vitro models, there was a good consistency between decrease in sodium spike amplitude in hiPSC-CM and QRS widening in isolated hearts. Patch clamp assay results showed that the QRS widening observed with PMX inhibitors is likely multifactorial, primarily due to NaV1.8 and NaV1.5 rate-dependent sodium blockade and\/or calcium channel-mediated mechanisms. In conclusion, early de-risking of QRS widening using a set of different in vitro assays allowed to identify novel PMX inhibitors with improved cardiac safety profile.<\/jats:p>","DOI":"10.1093\/toxsci\/kfae087","type":"journal-article","created":{"date-parts":[[2024,7,8]],"date-time":"2024-07-08T18:25:05Z","timestamp":1720463105000},"page":"321-330","source":"Crossref","is-referenced-by-count":1,"title":["Deconvoluting and derisking QRS complex widening to improve cardiac safety profile of novel plasmepsin X antimalarials"],"prefix":"10.1093","volume":"201","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6345-7989","authenticated-orcid":false,"given":"Annie","family":"Delaunois","sequence":"first","affiliation":[{"name":"UCB Biopharma SRL , 1420 Braine-l\u2019Alleud,","place":["Belgium"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alvaro","family":"Cardenas","sequence":"additional","affiliation":[{"name":"UCB Biopharma SRL , 1420 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