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Hypertrophic Cardiomyopathy
Published in Andreas P. Kalogeropoulos, Hal A. Skopicki, Javed Butler, Heart Failure, 2023
Ahmad Masri, Stephen B. Heitner
Perhexiline is an oral inhibitor of carnitine palmitoyl transferase I (CPT-1) which reduces fatty acid uptake into mitochondria, resulting in greater cellular dependence on carbohydrates for ATP production.93 Similar to diltiazem, perhexiline blocks the voltage-gated L-type calcium channels. Although a preclinical study94 and an early phase clinical study (METAL-HCM, NCT00500552)95 revealed favorable changes in the cardiac metabolome and improvement in exercise capacity compared to placebo, a multicenter phase-IIb clinical trial (NCT02862600) was terminated early due to lack of efficacy, and the drug has been abandoned as a potential therapy for nonobstructive HCM.
Substrates of Human CYP2D6
Published in Shufeng Zhou, Cytochrome P450 2D6, 2018
Perhexiline is a prophylactic antianginal drug used primarily in New Zealand and Australia (Horowitz et al. 1995). Perhexiline decreases fatty acid metabolism through the inhibition of carnitine palmitoyltransferase-1, an enzyme responsible for mitochondrial uptake of long-chain fatty acids (Ashrafian et al. 2007). The corresponding shift to greater carbohydrate utilization increases myocardial efficiency, and this oxygen-sparing effect may explain its antianginal efficacy. Perhexiline is a highly lipophilic drug (LogP = 5.87) with a large interindividual variability in its clearance and plasma concentrations (>100-fold). A therapeutic range of 0.15 to 0.6 mg/l has been established for plasma perhexiline at steady state (Cole et al. 1990). The saturable clearance of perhexiline shows a bimodal distribution, and the pharmacokinetics of perhexiline is nonlinear (Cole et al. 1990). Perhexiline is predominantly metabolized by CYP2D6 to two inactive metabolites cis-hydroxyperhexiline (M1) and trans-hydroxyperhexiline (M3), both existing as diastereomeric pairs (Figure 3.50) (Sorensen et al. 2003). The two main metabolites of perhexiline in the plasma and urine postdosing are M1 and M3. Dihydroxyperhexiline has also been identified in the urine. M1 is the primary determinant of perhexiline clearance and there is a large interindividual variability in metabolic clearance to M1 (Sallustio et al. 2002). The M1/perhexiline MR has been incorporated into therapeutic drug monitoring of perhexiline and in phenotype studies as it can readily separate PMs and EMs.
Current and emerging pharmacotherapy for the management of hypertrophic cardiomyopathy
Published in Expert Opinion on Pharmacotherapy, 2023
Akiva Rosenzveig, Neil Garg, Shiavax J. Rao, Amreen K. Kanwal, Arjun Kanwal, Wilbert S. Aronow, Matthew W. Martinez
Mutations in sarcomeric proteins in HCM lead to inefficient sarcomeric ATP utilization and increased energy demand [59]. To adapt to the increasing energy demand, there is an increased carbohydrate utilization [60]. Perhexiline is a carnitine palmitoyltransferase-1/2 (CPT-1/2) inhibitor that was discovered in the 1960s and has been historically used as an anti-anginal therapy owing to its coronary vasodilatory effects [61]. Inhibition of CPT-1 reduces fatty-acid uptake and increases carbohydrate dependance for production of ATP [62]. In preclinical studies, perhexiline increased myocardial efficiency by 30% [63]. METAL-HCM was a randomized, double-blinded, placebo-controlled, phase II study of symptomatic noHCM patients treated with perhexiline vs placebo that showed improvement in myocardial energetics and exercise capacity [64]. RESOLVE-HCM is a prospective, multicenter, double-blinded, placebo-controlled, randomized trial that is currently enrolling 60 patients with symptomatic HCM, with the primary endpoint being a change in left ventricular hypertrophy, assessed by utilizing cardiovascular magnetic resonance (CMR) imaging after 12-months of treatment with perhexiline [65].
Improving mitochondrial function in preclinical models of heart failure: therapeutic targets for future clinical therapies?
Published in Expert Opinion on Therapeutic Targets, 2023
Anna Gorący, Jakub Rosik, Joanna Szostak, Bartosz Szostak, Szymon Retfiński, Filip Machaj, Andrzej Pawlik
As ROS and mitochondrial disorders are crucial in HF development, the modifications of cardiac lipid metabolism have been investigated as promising therapeutic strategies. Perhexiline and etomoxir decrease FA oxidation by downregulating carnitine palmitoyl transferase 1 and 2, blocking the intake of long-chained FA into mitochondria [88,89]. Thereby, the oxidation of lipids is decreased, and simultaneously the cardiac metabolism shifts toward glycolysis. As the production of ATP from glucose requires less oxygen than oxidation of FA, this shift was predicted to improve cardiac function in patients with HF [89]. Despite the promising results of animal model studies and a small study on chronic HF patients, further studies were canceled due to drug side effects [88,90,91]. Despite the promising effects among patients with cardiomyopathy and chronic HF, the development of perhexiline was limited due to its narrow therapeutic window [90,92–94].
Hypertrophic cardiomyopathy: an up-to-date snapshot of the clinical drug development pipeline
Published in Expert Opinion on Investigational Drugs, 2022
Juan Tamargo, María Tamargo, Ricardo Caballero
These alterations led to the development of mitotropic drugs that shift cardiac metabolism from fatty acids to glucose that generates more ATP per unit of oxygen consumed, increase myocardial efficiency, and may improve cardiac function in patients with HCM [93,94]. Two antianginal drugs were evaluated: perhexiline, a carnitine palmitoyltransferase-1 inhibitor, and trimetazidine, a long-chain 3-ketoacyl-coenzyme A thiolase inhibitor. But despite the favorable results observed with perhexiline in preclinical [38] and in a phase 2 trial [99], a larger trial (NCT02862600) was prematurely terminated due to lack of efficacy and presence of adverse events. Similarly, trimetazidine was ineffective in improving exercise capacity in symptomatic patients with no-HCM [61]. But despite these negative results, two ongoing trials examine the effects of perhexiline and trimetazidine in HCM (Table 3) [88,89].