Electrophysiological and ECG Effects of Perhexiline, a Mixed Cardiac Ion Channel Inhibitor, Evaluated in Nonclinical Assays and in Healthy Subjects

• Published in: Journal of clinical pharmacology Vol. 61; no. 12; p. 1606
• Main Authors: Midei, Mark G, Darpo, Borje, Ayers, Greg, Brown, Randy, Couderc, Jean-Philippe, Daly, William, Ferber, Georg, Sager, Philip T, Camm, A John
• Format: Journal Article
• Language: English
• Published: England 01.12.2021
• Subjects: Adult; Calcium Channel Blockers - pharmacology; Cross-Over Studies; Dose-Response Relationship, Drug; Double-Blind Method; Electrocardiography - drug effects; Female; Humans; Male; Perhexiline - pharmacology; Pilot Projects; Young Adult; multi-channel block; concentration-effect modeling; JTpeak; QT; CiPA; perhexiline
• ISSN: 1552-4604
• DOI: 10.1002/jcph.1934

Perhexiline has been used to treat hypertrophic cardiomyopathy. In addition to its effect on carnitine-palmitoyltransferase-1, it has mixed ion channel effects through inhibition of several cardiac ion currents. Effects on cardiac ion channels expressed in mammalian cells were assayed using a manual patch-clamp 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 (150-600 ng/mL) with IC for hCav1.2 ∼ hERG < late hNav1.5. A significant APD shortening was observed in perhexiline-treated 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-designed part with a nested crossover comparison for the positive control. Perhexiline caused QTc prolongation, with the largest effect on ΔΔQTcF, 14.7 milliseconds at therapeutic concentrations and 25.6 milliseconds at supratherapeutic concentrations and a positive and statistically significant slope of the concentration-ΔΔQTcF relationship (0.018 milliseconds per ng/mL; 90%CI, 0.0119-0.0237 milliseconds per ng/mL). In contrast, the JTpeak interval was shortened with a negative concentration-JTpeak relationship, a pattern consistent with multichannel block. Further studies are needed to evaluate whether this results in a low proarrhythmic risk.