Electrophysiological and ECG Effects of Perhexiline, a Mixed Cardiac Ion Channel Inhibitor, Evaluated in Nonclinical Assays and in Healthy Subjects. (20th July 2021)

• Record Type: Journal Article
• Authors: Midei, Mark G.; Darpo, Borje; Ayers, Greg; Brown, Randy; Couderc, Jean‐Philippe; Daly, William; Ferber, Georg; Sager, Philip T.; Camm, A. John
• Is Part Of: Journal of clinical pharmacology. Volume 61:Number 12(2021)
• Page Start: 1606
• Page End: 1617
• Publication Date: 2021-07-20
• Subjects: CiPA -- concentration‐effect modeling -- JTpeak -- multi‐channel block -- perhexiline -- QT; Pharmacology -- Periodicals; Pharmacology -- Periodicals; Pharmacology, Clinical -- Periodicals; 615.1
• DOI: 10.1002/jcph.1934
• Languages: English
• ISSNs: 0091-2700

Abstract

Abstract: 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 IC50 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.