Midei, MG; Darpo, B; Ayers, G; Brown, R; Couderc, J-P; Daly, W; Ferber, G; Sager, PT; Camm, AJ
(2021)
Electrophysiological and ECG Effects of Perhexiline, a Mixed Cardiac Ion Channel Inhibitor, Evaluated in Nonclinical Assays and in Healthy Subjects.
J Clin Pharmacol, 61 (12).
pp. 1606-1617.
ISSN 1552-4604
https://doi.org/10.1002/jcph.1934
SGUL Authors: Camm, Alan John
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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.
Item Type: | Article |
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Additional Information: | This is the peer reviewed version of the following article: Midei, M.G., Darpo, B., Ayers, G., Brown, R., Couderc, J.-P., Daly, W., Ferber, G., Sager, P.T. and Camm, A.J. (2021), Electrophysiological and ECG Effects of Perhexiline, a Mixed Cardiac Ion Channel Inhibitor, Evaluated in Nonclinical Assays and in Healthy Subjects. The Journal of Clinical Pharmacology, 61: 1606-1617, which has been published in final form at https://doi.org/10.1002/jcph.1934. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions. |
Keywords: | Pharmacology & Pharmacy, 1115 Pharmacology and Pharmaceutical Sciences |
SGUL Research Institute / Research Centre: | Academic Structure > Molecular and Clinical Sciences Research Institute (MCS) |
Journal or Publication Title: | J Clin Pharmacol |
ISSN: | 1552-4604 |
Language: | eng |
Publisher License: | Publisher's own licence |
PubMed ID: | 34214210 |
Go to PubMed abstract | |
URI: | https://openaccess.sgul.ac.uk/id/eprint/113417 |
Publisher's version: | https://doi.org/10.1002/jcph.1934 |
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