J Clin Pharmacol. 2021 Jul 2. doi: 10.1002/jcph.1934. Online ahead of print.
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 manual patch-clamp technique, action potential duration (APD) were measured in ventricular trabeculae of human donor hearts, and ECG 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 Day 4 and 6, respectively. Guided by the results from the pilot, 104 subjects were enrolled in a parallel designed part with a nested cross-over comparison for the positive control. Perhexiline caused QTc prolongation, with a largest effect on ΔΔQTcF of 14.7 msec at therapeutic and 25.6 msec at supratherapeutic concentrations and a positive and statistically significant slope of the concentration-ΔΔQTcF relationship: 0.018 msec per ng/mL; 90% CI: 0.0119 to 0.0237. 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.
PMID:34214210 | DOI:10.1002/jcph.1934
