Absence of effect of steady state bempedoic acid on cardiac repolarization: Results of a thorough QT/QTc study in healthy volunteers

Abstract Bempedoic acid is an inhibitor of adenosine triphosphate–citrate lyase approved for use in adults with hypercholesterolemia. Nonclinical studies assessed binding to the human ether‐a‐go‐go–related gene (hERG) potassium channel in vitro and the effect of bempedoic acid on QT/QTc in cynomolgu...

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Autores principales:	Benny M. Amore, Clay T. Cramer, Diane E. MacDougall, William J. Sasiela, Maurice G. Emery
Formato:	article
Lenguaje:	EN
Publicado:	Wiley 2021
Materias:	Therapeutics. Pharmacology RM1-950 Public aspects of medicine RA1-1270
Acceso en línea:	https://doaj.org/article/d673bee841e24a1c9ed715ea6899fac6
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spelling	oai:doaj.org-article:d673bee841e24a1c9ed715ea6899fac62021-11-19T17:51:35ZAbsence of effect of steady state bempedoic acid on cardiac repolarization: Results of a thorough QT/QTc study in healthy volunteers1752-80621752-805410.1111/cts.13116https://doaj.org/article/d673bee841e24a1c9ed715ea6899fac62021-11-01T00:00:00Zhttps://doi.org/10.1111/cts.13116https://doaj.org/toc/1752-8054https://doaj.org/toc/1752-8062Abstract Bempedoic acid is an inhibitor of adenosine triphosphate–citrate lyase approved for use in adults with hypercholesterolemia. Nonclinical studies assessed binding to the human ether‐a‐go‐go–related gene (hERG) potassium channel in vitro and the effect of bempedoic acid on QT/QTc in cynomolgus monkeys. A randomized, double‐blind, parallel‐design clinical study assessed the effects of steady‐state bempedoic acid at a supratherapeutic dose (240 mg/day, 33.3% higher the180 mg/day therapeutic dose), placebo, and moxifloxacin (400 mg) in healthy subjects. In vitro binding potency for bempedoic acid to the hERG potassium channel was weak, with half‐maximal inhibition (IC50) estimated at greater than 1000 μM (>1670‐fold the bempedoic acid 180 mg/day steady‐state unbound maximum concentration). In monkeys, individual rate‐corrected QT intervals showed no time‐ or dose‐dependent changes up to 100 mg/kg of bempedoic acid. In human subjects, the upper 90% confidence interval (CI) for the difference in QTc interval, corrected using Fridericia’s formula (QTcF), between bempedoic acid and placebo was less than 5 msec at all time points. Concentration‐QTcF analysis showed that maximum bempedoic acid concentration at steady‐state was attained at a median 2.1 h postdose, and the predicted mean change (90% CI) in QTcF at the observed mean bempedoic acid concentration 2 h postdose was −0.5 (−5.0, 4.0) msec. The lower bound of the moxifloxacin 90% CI exceeded 5 msec at prespecified time points, establishing study sensitivity. Steady‐state bempedoic acid at a supratherapeutic dose of 240 mg was generally well‐tolerated and not associated with QTc prolongation in healthy subjects.Benny M. AmoreClay T. CramerDiane E. MacDougallWilliam J. SasielaMaurice G. EmeryWileyarticleTherapeutics. PharmacologyRM1-950Public aspects of medicineRA1-1270ENClinical and Translational Science, Vol 14, Iss 6, Pp 2487-2496 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Therapeutics. Pharmacology RM1-950 Public aspects of medicine RA1-1270
spellingShingle	Therapeutics. Pharmacology RM1-950 Public aspects of medicine RA1-1270 Benny M. Amore Clay T. Cramer Diane E. MacDougall William J. Sasiela Maurice G. Emery Absence of effect of steady state bempedoic acid on cardiac repolarization: Results of a thorough QT/QTc study in healthy volunteers
description	Abstract Bempedoic acid is an inhibitor of adenosine triphosphate–citrate lyase approved for use in adults with hypercholesterolemia. Nonclinical studies assessed binding to the human ether‐a‐go‐go–related gene (hERG) potassium channel in vitro and the effect of bempedoic acid on QT/QTc in cynomolgus monkeys. A randomized, double‐blind, parallel‐design clinical study assessed the effects of steady‐state bempedoic acid at a supratherapeutic dose (240 mg/day, 33.3% higher the180 mg/day therapeutic dose), placebo, and moxifloxacin (400 mg) in healthy subjects. In vitro binding potency for bempedoic acid to the hERG potassium channel was weak, with half‐maximal inhibition (IC50) estimated at greater than 1000 μM (>1670‐fold the bempedoic acid 180 mg/day steady‐state unbound maximum concentration). In monkeys, individual rate‐corrected QT intervals showed no time‐ or dose‐dependent changes up to 100 mg/kg of bempedoic acid. In human subjects, the upper 90% confidence interval (CI) for the difference in QTc interval, corrected using Fridericia’s formula (QTcF), between bempedoic acid and placebo was less than 5 msec at all time points. Concentration‐QTcF analysis showed that maximum bempedoic acid concentration at steady‐state was attained at a median 2.1 h postdose, and the predicted mean change (90% CI) in QTcF at the observed mean bempedoic acid concentration 2 h postdose was −0.5 (−5.0, 4.0) msec. The lower bound of the moxifloxacin 90% CI exceeded 5 msec at prespecified time points, establishing study sensitivity. Steady‐state bempedoic acid at a supratherapeutic dose of 240 mg was generally well‐tolerated and not associated with QTc prolongation in healthy subjects.
format	article
author	Benny M. Amore Clay T. Cramer Diane E. MacDougall William J. Sasiela Maurice G. Emery
author_facet	Benny M. Amore Clay T. Cramer Diane E. MacDougall William J. Sasiela Maurice G. Emery
author_sort	Benny M. Amore
title	Absence of effect of steady state bempedoic acid on cardiac repolarization: Results of a thorough QT/QTc study in healthy volunteers
title_short	Absence of effect of steady state bempedoic acid on cardiac repolarization: Results of a thorough QT/QTc study in healthy volunteers
title_full	Absence of effect of steady state bempedoic acid on cardiac repolarization: Results of a thorough QT/QTc study in healthy volunteers
title_fullStr	Absence of effect of steady state bempedoic acid on cardiac repolarization: Results of a thorough QT/QTc study in healthy volunteers
title_full_unstemmed	Absence of effect of steady state bempedoic acid on cardiac repolarization: Results of a thorough QT/QTc study in healthy volunteers
title_sort	absence of effect of steady state bempedoic acid on cardiac repolarization: results of a thorough qt/qtc study in healthy volunteers
publisher	Wiley
publishDate	2021
url	https://doaj.org/article/d673bee841e24a1c9ed715ea6899fac6
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Absence of effect of steady state bempedoic acid on cardiac repolarization: Results of a thorough QT/QTc study in healthy volunteers

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