A systematic strategy for estimating hERG block potency and its implications in a new cardiac safety paradigm

Ridder, Bradley J.; Leishman, Derek J.; Bridgland-Taylor, Matthew; Samieegohar, Mohammadreza; Han, Xiaomei; Wu, Wendy; Randolph, Aaron; Tran, P.; Sheng, Jiansong; Danker, Timm; Lindqvist, Anders; Konrad, Daniel; Hebeisen, Simon; Polonchuk, Liudmila; Gissinger, Evgenia; Renganathan, Muthukrishnan; Koci, Bryan; Wei, Haiyang; Fan, Jing‐Song; Lévesque, Paul; Kwagh, Jae; Imredy, John P.; Zhai, Jin; Rogers, Marc; Humphries, Edward; Kirby, R. Jason; Stoelzle-Feix, Sonja; Brinkwirth, Nina; Rotordam, Maria Giustina; Becker, Norbert; Friis, Søren; Rapedius, Markus; Goetze, Tom A.; Strassmaier, Tim; Okeyo, George; Kramer, James; Kuryshev, Yuri A.; Wu, Caiyun; Himmel, Herbert M.; Mirams, Gary R.; Strauss, David G.; Bardenet, Rémi; Li, Zhihua

doi:10.1016/j.taap.2020.114961

Cited by 32 publications

(41 citation statements)

References 30 publications

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“… d Ridder et al . sensitivity and specificity numbers come from different hERG margin thresholds from that dataset 11 …”

Section: Use Of Double‐negative Nonclinical Data ‐ Comments On Proposmentioning

confidence: 99%

“…when a hERG safety margin of 30 is used ( Table 1 ). 11 The Ridder et al . data come from a 13‐site prospective study with a standardized voltage waveform protocol on automated patch clamp systems including the 28 drugs from the Comprehensive in vitro Proarrhythmia Assay (CiPA) initiative.…”

Section: Use Of Double‐negative Nonclinical Data ‐ Comments On Proposmentioning

confidence: 99%

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Translational Models and Tools to Reduce Clinical Trials and Improve Regulatory Decision Making for QTc and Proarrhythmia Risk (ICH E14/S7B Updates)

Strauss

et al. 2021

Clin Pharma and Therapeutics

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After multiple drugs were removed from the market secondary to drug‐induced torsade de pointes (TdP) risk, the International Council for Harmonisation (ICH) released guidelines in 2005 that focused on the nonclinical (S7B) and clinical (E14) assessment of surrogate biomarkers for TdP. Recently, Vargas et al. published a pharmaceutical‐industry perspective making the case that “double‐negative” nonclinical data (negative in vitro hERG and in vivo heart‐rate corrected QT (QTc) assays) are associated with such low probability of clinical QTc prolongation and TdP that potentially all double‐negative drugs would not need detailed clinical QTc evaluation. Subsequently, the ICH released a new E14/S7B Draft Guideline containing Questions and Answers (Q&As) that defined ways that double‐negative nonclinical data could be used to reduce the number of “Thorough QT” (TQT) studies and reach a low‐risk determination when a TQT or equivalent could not be performed. We review the Vargas et al. proposal in the context of what was contained in the ICH E14/S7B Draft Guideline and what was proposed by the ICH E14/S7B working group for a “stage 2” of updates (potential expanded roles for nonclinical data and details for assessing TdP risk of QTc‐prolonging drugs). Although we do not agree with the exact probability statistics in the Vargas et al. paper because of limitations in the underlying datasets, we show how more modest predictive value of individual assays could still result in low probability for TdP with double‐negative findings. Furthermore, we expect that the predictive value of the nonclinical assays will improve with implementation of the new ICH E14/S7B Draft Guideline.

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“… d Ridder et al . sensitivity and specificity numbers come from different hERG margin thresholds from that dataset 11 …”

Section: Use Of Double‐negative Nonclinical Data ‐ Comments On Proposmentioning

confidence: 99%

Section: Use Of Double‐negative Nonclinical Data ‐ Comments On Proposmentioning

confidence: 99%

Translational Models and Tools to Reduce Clinical Trials and Improve Regulatory Decision Making for QTc and Proarrhythmia Risk (ICH E14/S7B Updates)

Strauss

et al. 2021

Clin Pharma and Therapeutics

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“…Despite the impressive findings obtained from in silico and in vitro models, there are discrepancies between model predictions and experimental observations, in particular for multichannel blocking drugs (Britton et al, 2017). For in vitro models, results depend on the experimental protocol, and quality standards as well as experimental conditions need to be taken into account (Ridder et al, 2020). Consequently, the fourth CiPA component stipulates the complementary use of early, intensive clinical ECG monitoring to assess cardiac effects in humans, to confirm model predictions and to identify potential unanticipated threats.…”

Section: Introductionmentioning

confidence: 99%

Identification of Drug-Induced Multichannel Block and Proarrhythmic Risk in Humans Using Continuous T Vector Velocity Effect Profiles Derived From Surface Electrocardiograms

et al. 2020

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Bystricky et al. TVV Drug Effect Profiles effects throughout the entire ventricular repolarization interval. It enables the evaluation of drug-induced blocks of multiple cardiac repolarization currents from clinical ECGs. The proposed p zero parameter enhances identification of the proarrhythmic risk of a drug beyond QT prolongation, and therefore constitutes an important tool for cardiac arrhythmia risk assessment.

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“…To the best of our knowledge, previous experimental and observational studies of the potential proarrhythmic effects of CQ and AZM have not considered the role of beta-adrenergic receptor stimulation. Computational modeling has increasingly been used in cardiac safety pharmacology to predict the proarrhythmic effect of novel compounds (Qu et al, 2019;Li et al, 2020;Ridder et al, 2020). Therefore, this study aimed to assess the potential cellular proarrhythmic effects of CQ and AZM in both the absence and presence of beta-adrenergic receptor stimulation using a population of detailed in silico models of ventricular electrophysiology.…”

Section: Introductionmentioning

confidence: 99%

Beta-Adrenergic Receptor Stimulation Modulates the Cellular Proarrhythmic Effects of Chloroquine and Azithromycin

Sutanto

Heijman

2020

Front. Physiol.

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The antimalarial drug, chloroquine (CQ), and antimicrobial drug, azithromycin (AZM), have received significant attention during the COVID-19 pandemic. Both drugs can alter cardiac electrophysiology and have been associated with drug-induced arrhythmias. Meanwhile, sympathetic activation is commonly observed during systemic inflammation and oxidative stress (e.g., in SARS-CoV-2 infection) and may influence the electrophysiological effects of CQ and AZM. Here, we investigated the effect of beta-adrenergic stimulation on proarrhythmic properties of CQ and AZM using detailed in silico models of ventricular electrophysiology. Concentration-dependent alterations in ion-channel function were incorporated into the Heijman canine and O'Hara-Rudy human ventricular cardiomyocyte models. Single and combined drug effects on action-potential (AP) properties were analyzed using a population of 1,000 models accommodating inter-individual variability. Sympathetic stimulation was simulated by increasing pacing rate and experimentally validated isoproterenol (ISO)-induced changes in ion-channel function. In the canine ventricular model at 1 Hz pacing, therapeutic doses of CQ and AZM (5 and 20 μM, respectively) individually prolonged AP duration (APD) by 33 and 13%. Their combination produced synergistic APD prolongation (+161%) with incidence of proarrhythmic early afterdepolarizations in 53.5% of models. Increasing the pacing frequency to 2 Hz shortened APD and together with 1 μM ISO counteracted the drug-induced APD prolongation. No afterdepolarizations occurred following increased rate and simulated application of ISO. Similarly, CQ and AZM individually prolonged APD by 43 and 29% in the human ventricular cardiomyocyte model, while their combination prolonged APD by 76% without causing early afterdepolarizations. Consistently, 1 μM ISO at 2 Hz pacing counteracted the drug-induced APD prolongation. Increasing the I Ca,L window current produced afterdepolarizations, which were exacerbated by ISO. In both models, reduced extracellular K + reduced the repolarization reserve and increased drug effects. In conclusion, CQ-and AZM-induced proarrhythmia is promoted by conditions with reduced repolarization reserve. Sympathetic stimulation limits drug-induced APD prolongation, suggesting the potential importance of heart rate and autonomic status monitoring in particular conditions (e.g., COVID-19).

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A systematic strategy for estimating hERG block potency and its implications in a new cardiac safety paradigm

Cited by 32 publications

References 30 publications

Translational Models and Tools to Reduce Clinical Trials and Improve Regulatory Decision Making for QTc and Proarrhythmia Risk (ICH E14/S7B Updates)

Translational Models and Tools to Reduce Clinical Trials and Improve Regulatory Decision Making for QTc and Proarrhythmia Risk (ICH E14/S7B Updates)

Identification of Drug-Induced Multichannel Block and Proarrhythmic Risk in Humans Using Continuous T Vector Velocity Effect Profiles Derived From Surface Electrocardiograms

Beta-Adrenergic Receptor Stimulation Modulates the Cellular Proarrhythmic Effects of Chloroquine and Azithromycin

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