The impact of drug-induced QT interval prolongation on drug discovery and development

  title={The impact of drug-induced QT interval prolongation on drug discovery and development},
  author={Bernard Fermini and Anthony A Fossa},
  journal={Nature Reviews Drug Discovery},
During the past decade, a number of non-cardiovascular drugs have had their label revised or have been withdrawn from the market because of unexpected post-marketing reports of sudden cardiac death associated with a prolongation of the QT interval, and an increased propensity to develop a ventricular tachyarrhythmia called Torsades de Pointes. Although a direct link between QT interval prolongation and arrhythmogenesis is still unclear, QT prolongation is now the subject of increased regulatory… 

Reverse engineering of drug-induced QT(c) interval prolongation: a systems pharmacology approach

  • Biology, Medicine
  • 2017
QT prolongation and the risk of ventricular arrhythmias in humans remain a major concern during drug development despite the advancement of numerous methodologies to detect the potential for

Drugs, QT Interval Prolongation and ICH E14

This paper provides an overview commentary on some contentious or ambiguous aspects of draft ICH E14 with a view to stimulating a debate and inviting scientifically supported comments from stakeholders in order to ensure that the application of the I CH E14 strategy does not result in either restriction in the use of a potentially beneficial drug or approval of an otherwise hazardous drug without the restrictions required to promote its safe use.

Genetics of drug-induced QT prolongation: evaluating the evidence for pharmacodynamic variants.

The high level of evidence for pharmacodynamic genetic variants associated with diLQTS supports current consideration as risk factors for patients that will be prescribed a QT-prolonging drug.

Keeping the rhythm: hERG and beyond in cardiovascular safety pharmacology

An overview of TdP, including the cardiac action potential and the ion channels involved in it, is provided as well as on the relevance and interpretation of in vitro hERG channel data and their impact for drug discovery projects.

Comparative Study of Diuretics & Antimalarial Drugs on QT - Interval Prolongation in Rat

Some drugs like diuretics and antimalarial has also been reported to be preclinically and clinically induce long QT Syndrome and further torsade de point and leads to sudden death.



The QT interval.

The preclinical assessment of the risk for QT interval prolongation.

Different methodological approaches are presented in this paper and experimental protocols are suggested and a strategy for the preclinical assessment of the potential of a molecule for QT interval prolongation is presented.

[Draft ICH guideline S7B: guideline on safety pharmacology studies for assessing the potential for delayed ventricular repolarization (QT interval prolongation) by human pharmaceuticals].

  • M. Hashimoto
  • Medicine
    Nihon yakurigaku zasshi. Folia pharmacologica Japonica
  • 2003
This guideline is being developed to provide the general nonclinical testing strategy for evaluating the potential risk of QT prolongation and presents some major principles for in vitro and in vivo electrophysiology studies and chemical/pharmacological class information.

Drugs that prolong QT interval as an unwanted effect: assessing their likelihood of inducing hazardous cardiac dysrhythmias

The decision as to whether the potential benefit of a new drug outweighs the cardiac risk inherent in its therapeutic use should be made in the light of the condition that it is expected to treat and with reference to alternative drug therapies.

A structural basis for drug-induced long QT syndrome.

Drug‐induced prolongation of the QT interval: regulatory dilemmas and implications for approval and labelling of a new chemical entity

  • R. Shah
  • Medicine
    Fundamental & clinical pharmacology
  • 2002
The views expressed in this paper are those of the author and do not necessarily represent the views or the opinions of Medicines Control Agency, other regulatory authorities or any of their advisory

Cellular mechanisms underlying the long QT syndrome.

The available data suggest that that the principal problem with thelong QT syndrome is not long QT intervals but rather the dispersion of repolarization that often accompanies prolongation of the QT interval.

The Canine Purkinje Fiber: An In Vitro Model System for Acquired Long QT Syndrome and Drug-Induced Arrhythmogenesis

This Purkinje fiber model detects six of seven drugs linked clinically to acquired long QT syndrome and torsade de pointes, and clears each of five drugs not associated with repolarization abnormalities (overall 92% accuracy), validating the utility of this Purkinjen fiber model in the preclinical evaluation of QT prolongation and proarrhythmic risk by noncardiac drugs.

Mechanism of the cardiotoxic actions of terfenadine.

In vitro cardiac electrophysiologic studies found that terfenadine is equipotent to quinidine as a blocker of the delayed rectifier potassium current in isolated feline myocytes, which indicates that episodes of torsades de pointes are most likely the result of a quinidinelike action of the parent drug and of factors that impair the normally rapid metabolism of terfenADine.