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Effects on cardiac ion channels expressed in mammalian cells were assayed using a manual patch\u2010clamp technique, action potential duration (APD) was measured in ventricular trabeculae of human donor hearts, and electrocardiogram effects were evaluated in healthy subjects in a thorough QT (TQT) study. Perhexiline blocked several cardiac ion currents at concentrations within the therapeutic range (150\u2010600 ng\/mL) with IC<jats:sub>50<\/jats:sub> for hCav1.2 \u223c hERG &lt; late hNav1.5. A significant APD shortening was observed in perhexiline\u2010treated cardiomyocytes. The TQT study was conducted with a pilot part in 9 subjects to evaluate a dosing schedule that would achieve therapeutic and supratherapeutic perhexiline plasma concentrations on days 4 and 6, respectively. Guided by the results from the pilot, 104 subjects were enrolled in a parallel\u2010designed part with a nested crossover comparison for the positive control. Perhexiline caused QTc prolongation, with the largest effect on \u0394\u0394QTcF, 14.7\u00a0milliseconds at therapeutic concentrations and 25.6\u00a0milliseconds at supratherapeutic concentrations and a positive and statistically significant slope of the concentration\u2010\u0394\u0394QTcF relationship (0.018 milliseconds per ng\/mL; 90%CI, 0.0119\u20100.0237 milliseconds per ng\/mL). In contrast, the JTpeak interval was shortened with a negative concentration\u2010JTpeak relationship, a pattern consistent with multichannel block. Further studies are needed to evaluate whether this results in a low proarrhythmic risk.<\/jats:p>","DOI":"10.1002\/jcph.1934","type":"journal-article","created":{"date-parts":[[2021,7,2]],"date-time":"2021-07-02T16:39:00Z","timestamp":1625243940000},"page":"1606-1617","update-policy":"http:\/\/dx.doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Electrophysiological and ECG Effects of Perhexiline, a Mixed Cardiac Ion Channel Inhibitor, Evaluated in Nonclinical Assays and in Healthy Subjects"],"prefix":"10.1002","volume":"61","author":[{"given":"Mark G.","family":"Midei","sequence":"first","affiliation":[{"name":"Heart Metabolics  Dublin Ireland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Borje","family":"Darpo","sequence":"additional","affiliation":[{"name":"ERT  Rochester New York USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Greg","family":"Ayers","sequence":"additional","affiliation":[{"name":"Heart Metabolics  Dublin Ireland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Randy","family":"Brown","sequence":"additional","affiliation":[{"name":"ERT  Rochester New York USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jean\u2010Philippe","family":"Couderc","sequence":"additional","affiliation":[{"name":"ERT  Rochester New York USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"William","family":"Daly","sequence":"additional","affiliation":[{"name":"Heart Metabolics  Dublin Ireland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Georg","family":"Ferber","sequence":"additional","affiliation":[{"name":"Statistik Georg Ferber GmbH  Riehen Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Philip T.","family":"Sager","sequence":"additional","affiliation":[{"name":"Department of Medicine, Cardiovascular Research Institute Stanford University  Palo Alto California USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"A. 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