The Challenges of Predicting Drug-Induced QTc Prolongation in Humans.
QT prolongation
Torsades de Pointes (TdP)
discordance
hERG
pharmacokinetics
proarrhythmia
regulatory
sensitivity
specificity
Journal
Toxicological sciences : an official journal of the Society of Toxicology
ISSN: 1096-0929
Titre abrégé: Toxicol Sci
Pays: United States
ID NLM: 9805461
Informations de publication
Date de publication:
26 04 2022
26 04 2022
Historique:
pubmed:
12
2
2022
medline:
29
4
2022
entrez:
11
2
2022
Statut:
ppublish
Résumé
The content of this article derives from a Health and Environmental Sciences Institute (HESI) consortium with a focus to improve cardiac safety during drug development. A detailed literature review was conducted to evaluate the concordance between nonclinical repolarization assays and the clinical thorough QT (TQT) study. Food and Drug Administration and HESI developed a joint database of nonclinical and clinical data, and a retrospective analysis of 150 anonymized drug candidates was reviewed to compare the performance of 3 standard nonclinical assays with clinical TQT study findings as well as investigate mechanism(s) potentially responsible for apparent discrepancies identified. The nonclinical assays were functional (IKr) current block (Human ether-a-go-go related gene), action potential duration, and corrected QT interval in animals (in vivo corrected QT). Although these nonclinical assays demonstrated good specificity for predicting negative clinical QT prolongation, they had relatively poor sensitivity for predicting positive clinical QT prolongation. After review, 28 discordant TQT-positive drugs were identified. This article provides an overview of direct and indirect mechanisms responsible for QT prolongation and theoretical reasons for lack of concordance between clinical TQT studies and nonclinical assays. We examine 6 specific and discordant TQT-positive drugs as case examples. These were derived from the unique HESI/Food and Drug Administration database. We would like to emphasize some reasons for discordant data including, insufficient or inadequate nonclinical data, effects of the drug on other cardiac ion channels, and indirect and/or nonelectrophysiological effects of drugs, including altered heart rate. We also outline best practices that were developed based upon our evaluation.
Identifiants
pubmed: 35148401
pii: 6527179
doi: 10.1093/toxsci/kfac013
pmc: PMC9041548
doi:
Types de publication
Journal Article
Review
Langues
eng
Sous-ensembles de citation
IM
Pagination
3-24Informations de copyright
© The Author(s) 2022. Published by Oxford University Press on behalf of the Society of Toxicology.
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