Pharmacological and Regulatory Aspects of QT Prolongation

Ponti, Fabrizio De

doi:10.1002/9783527621460.ch3

Cited by 7 publications

(5 citation statements)

References 157 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Computational methods like in silico modeling, molecular docking, and dynamic simulation could be particularly valuable in such cases. positive hERG liability [24,25]. However, in silico tools remain to be of great help in filtering out these compounds and, thus, have reduced the incidence of potent hERG blockers in industrial drug discovery programs [26].…”

Section: Introductionmentioning

confidence: 99%

Binding modes of hERG blockers: an unsolved mystery in the drug design arena

Kalyaanamoorthy

Barakat

2017

Expert Opinion on Drug Discovery

View full text Add to dashboard Cite

Section: Introductionmentioning

confidence: 99%

Binding modes of hERG blockers: an unsolved mystery in the drug design arena

Kalyaanamoorthy

Barakat

2017

Expert Opinion on Drug Discovery

View full text Add to dashboard Cite

“…De Ponti described the pharmacological and regulatory aspects of QT prolongation, and pointed out that hERG inhibition is a necessary, but not sufficient, cause for drug-induced TdP: drugs that prolong QT interval are hERG inhibitors, but several hERG inhibitors do not prolong the QT interval. 71 A major risk factor is the coadministration with inhibitors of metabolizing enzymes, which may increase the exposure of hERG inhibitors by decreasing their metabolism. Indeed, this mechanism initially led to the withdrawal of terfenadine, and later on of other hERG inhibitors, from the market.…”

Section: ■ Resultsmentioning

confidence: 99%

“…TdP related cardiac events and fatalities were generally observed after overdosing or after “unpredictable” changes in plasma drug concentrations triggered by drug–drug interactions. De Ponti described the pharmacological and regulatory aspects of QT prolongation, and pointed out that hERG inhibition is a necessary, but not sufficient, cause for drug-induced TdP: drugs that prolong QT interval are hERG inhibitors, but several hERG inhibitors do not prolong the QT interval . A major risk factor is the coadministration with inhibitors of metabolizing enzymes, which may increase the exposure of hERG inhibitors by decreasing their metabolism.…”

Section: Discussionmentioning

confidence: 99%

QSAR Modeling and Data Mining Link Torsades de Pointes Risk to the Interplay of Extent of Metabolism, Active Transport, and hERG Liability

et al. 2012

View full text Add to dashboard Cite

We collected 1173 hERG patch clamp (PC) data (IC50) from the literature to derive twelve classification models for hERG inhibition, covering a large variety of chemical descriptors and classification algorithms. Models were generated using 545 molecules and validated through 258 external molecules tested in PC experiments. We also evaluated the suitability of the best models to predict the activity of 26 proprietary compounds tested in radioligand binding displacement (RBD). Results proved the necessity to use multiple validation sets for a true estimation of model accuracy and demonstrated that using various descriptors and algorithms improves the performance of ligand-based models. Intriguingly, one of the most accurate models uncovered an unexpected link between extent of metabolism and hERG liability. This hypothesis was fairly reinforced by using the Biopharmaceutics Drug Disposition Classification System (BDDCS) that recognized 94% of the hERG inhibitors as extensively metabolized in vivo. Data mining suggested that high Torsades de Pointes (TdP) risk results from an interplay of hERG inhibition, extent of metabolism, active transport, and possibly solubility. Overall, these new findings might improve both the decision making skills of pharmaceutical scientists to mitigate hERG liability during the drug discovery process and the TdP risk assessment during drug development.

show abstract

“…The regulatory landscape to date has unquestionably been successful in one important regard: no drug with unanticipated liability for TdP has entered the market since its implementation. However, de Ponti estimated that “as many as 60% of new molecular entities developed as potential therapeutic agents, when assayed for I Kr blocking liability, test positive and are thus abandoned early in development.” This is unfortunate because, in some cases, a sufficient margin exists between therapeutic plasma concentrations and the concentrations that cause I Kr blockade and blockade of different channels may lead to lack of proarrhythmic risk, even to antiarrhythmic properties (eg, amiodarone, ranolazine). Verapamil, a potent I Kr blocker, does not cause QTc prolongation (except possibly at very high intravenous exposures), likely because it blocks calcium current as well.…”

Section: Potential Future Modifications To the Regulatory Landscapementioning

confidence: 99%

Drug‐induced Proarrhythmia and Torsade de Pointes: A Primer for Students and Practitioners of Medicine and Pharmacy

Turner

Rodríguez

Mantovani

et al. 2018

The Journal of Clinical Pharma

View full text Add to dashboard Cite

Multiple marketing withdrawals due to proarrhythmic concerns occurred in the United States, Canada, and the United Kingdom in the late 1980s to early 2000s. This primer reviews the clinical implications of a drug's identified proarrhythmic liability, the issues associated with these safety-related withdrawals, and the actions taken by the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) and by regulatory agencies in terms of changing drug development practices and introducing new nonclinical and clinical tests to asses proarrhythmic liability. ICH Guidelines S7B and E14 were released in 2005. Since then, they have been adopted by many regional regulatory authorities and have guided nonclinical and clinical proarrhythmic cardiac safety assessments during drug development. While this regulatory paradigm has been successful in preventing drugs with unanticipated potential for inducing the rare but potentially fatal polymorphic ventricular arrhythmia torsade de pointes from entering the market, it has led to the termination of drug development programs for other potentially useful medicines because of isolated results from studies with limited predictive value. Research efforts are now exploring alternative approaches to better predict potential proarrhythmic liabilities. For example, in the domain of human electrocardiographic assessments, concentration-response modeling conducted during phase 1 clinical development has recently become an accepted alternate primary methodology to the ICH E14 "thorough QT/QTc" study for defining a drug's corrected QT interval prolongation liability under certain conditions. When a drug's therapeutic benefit is considered important at a public health level but there is also an identified proarrhythmic liability that may result from administration of the single drug in certain individuals and/or drug-drug interactions, marketing approval will be accompanied by appropriate directions in the drug's prescribing information. Health-care professionals in the fields of medicine and pharmacy need to consider the prescribing information in conjunction with individual patients' clinical characteristics and concomitant medications when prescribing and dispensing such drugs.

show abstract

Pharmacological and Regulatory Aspects of QT Prolongation

Cited by 7 publications

References 157 publications

Binding modes of hERG blockers: an unsolved mystery in the drug design arena

Binding modes of hERG blockers: an unsolved mystery in the drug design arena

QSAR Modeling and Data Mining Link Torsades de Pointes Risk to the Interplay of Extent of Metabolism, Active Transport, and hERG Liability

Drug‐induced Proarrhythmia and Torsade de Pointes: A Primer for Students and Practitioners of Medicine and Pharmacy

Contact Info

Product

Resources

About