hERG Inhibitors with Similar Potency But Different Binding Kinetics Do Not Pose the Same Proarrhythmic Risk: Implications for Drug Safety Assessment

Veroli, Giovanni Y. Di; Davies, Mark; Zhang, Henggui; Abi‐Gerges, Najah; Boyett, Mark R.

doi:10.1111/jce.12289

Cited by 65 publications

(68 citation statements)

References 28 publications

(58 reference statements)

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“…2b). Simulations of LQTS2 in the cable produced a slurred upstroke for the T wave but did not produce notching, consistent with previous observations from ourselves as well as other groups [20][21][22] . When we extended our simulations to the whole ventricle, which included cellular heterogeneity and details of tissue architecture (see Supplementary Fig.…”

Section: Resultssupporting

confidence: 80%

Multiscale cardiac modelling reveals the origins of notched T waves in long QT syndrome type 2

et al. 2014

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The heart rhythm disorder long QT syndrome (LQTS) can result in sudden death in the young or remain asymptomatic into adulthood. The features of the surface electrocardiogram (ECG), a measure of the electrical activity of the heart, can be equally variable in LQTS patients, posing well-described diagnostic dilemmas. Here we report a correlation between QT interval prolongation and T-wave notching in LQTS2 patients and use a novel computational framework to investigate how individual ionic currents, as well as cellular and tissue level factors, contribute to notched T waves. Furthermore, we show that variable expressivity of ECG features observed in LQTS2 patients can be explained by as little as 20% variation in the levels of ionic conductances that contribute to repolarization reserve. This has significant implications for interpretation of whole-genome sequencing data and underlies the importance of interpreting the entire molecular signature of disease in any given individual.

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Section: Resultssupporting

confidence: 80%

Multiscale cardiac modelling reveals the origins of notched T waves in long QT syndrome type 2

et al. 2014

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“…10,11 Dofetilide and cisapride have vastly different unbinding rates because of the tendency of dofetilide but not cisapride to be trapped within the hERG channel. 12 Although it has been shown theoretically that trapped drugs may have more proarrhythmia liability compared with nontrapped drugs with similar hERG-blocking potency, 13,14 no attempt has been made to classify TdP risk using experimentally derived data on drug-channel interactions in an in silico model.…”

mentioning

confidence: 99%

Improving the In Silico Assessment of Proarrhythmia Risk by Combining hERG (Human Ether-à-go-go-Related Gene) Channel–Drug Binding Kinetics and Multichannel Pharmacology

Dutta

Sheng

et al. 2017

Circ: Arrhythmia and Electrophysiology

166

341

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Background-The current proarrhythmia safety testing paradigm, although highly efficient in preventing new torsadogenic drugs from entering the market, has important limitations that can restrict the development and use of valuable new therapeutics. The CiPA (Comprehensive in vitro Proarrhythmia Assay) proposes to overcome these limitations by evaluating drug effects on multiple cardiac ion channels in vitro and using these data in a predictive in silico model of the adult human ventricular myocyte. A set of drugs with known clinical torsade de pointes risk was selected to develop and calibrate the in silico model. Methods and Results-Manual patch-clamp data assessing drug effects on expressed cardiac ion channels were integrated into the O'Hara-Rudy myocyte model modified to include dynamic drug-hERG channel (human Ether-à-go-go-Related Gene) interactions. Together with multichannel pharmacology data, this model predicts that compounds with high torsadogenic risk are more likely to be trapped within the hERG channel and show stronger reverse use dependency of action potential prolongation. Furthermore, drug-induced changes in the amount of electronic charge carried by the late sodium and L-type calcium currents was evaluated as a potential metric for assigning torsadogenic risk. Conclusions-Modeling dynamic drug-hERG channel interactions and multi-ion channel pharmacology improves the prediction of torsadogenic risk. With further development, these methods have the potential to improve the regulatory assessment of drug safety models under the CiPA paradigm. (Circ Arrhythm Electrophysiol. 2017;10:e004628.

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“…When considering drugs with an even lower affinity than clozapine and so faster time constants of unblock, then it may not be possible to get accurate estimates of the fast components unless we explicitly include a drug diffusion term in the model. It is widely accepted that an understanding of the kinetics of drug interactions with the K v 11.1 channel is fundamental to our insight into the proarrhythmic propensity of these drugs (Di Veroli et al, 2013a). In this study, we have provided the first direct measurement of the kinetics of drug binding to unbinding from K v 11.1 channels at high temporal resolution.…”

Section: Discussionmentioning

confidence: 85%

Kinetics of Drug Interaction with the K_v11.1 Potassium Channel

et al. 2014

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hERG Inhibitors with Similar Potency But Different Binding Kinetics Do Not Pose the Same Proarrhythmic Risk: Implications for Drug Safety Assessment

Abstract: Our study demonstrates the need for screening for hERG binding configurations rather than potency alone. It also demonstrates the potential link between hERG, drug mode of action and TdP, and the need to question the current regulatory guidance.

Cited by 65 publications

References 28 publications

Multiscale cardiac modelling reveals the origins of notched T waves in long QT syndrome type 2

Multiscale cardiac modelling reveals the origins of notched T waves in long QT syndrome type 2

Improving the In Silico Assessment of Proarrhythmia Risk by Combining hERG (Human Ether-à-go-go-Related Gene) Channel–Drug Binding Kinetics and Multichannel Pharmacology

Kinetics of Drug Interaction with the K_v11.1 Potassium Channel

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hERG Inhibitors with Similar Potency But Different Binding Kinetics Do Not Pose the Same Proarrhythmic Risk: Implications for Drug Safety Assessment

Abstract: Our study demonstrates the need for screening for hERG binding configurations rather than potency alone. It also demonstrates the potential link between hERG, drug mode of action and TdP, and the need to question the current regulatory guidance.

Cited by 65 publications

References 28 publications

Multiscale cardiac modelling reveals the origins of notched T waves in long QT syndrome type 2

Multiscale cardiac modelling reveals the origins of notched T waves in long QT syndrome type 2

Improving the In Silico Assessment of Proarrhythmia Risk by Combining hERG (Human Ether-à-go-go-Related Gene) Channel–Drug Binding Kinetics and Multichannel Pharmacology

Kinetics of Drug Interaction with the Kv11.1 Potassium Channel

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Kinetics of Drug Interaction with the K_v11.1 Potassium Channel