ArticleToxicology and applied pharmacology2020
A systematic strategy for estimating hERG block potency and its implications in a new cardiac safety paradigm.
Article in Toxicology and applied pharmacology, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 26 papers.
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Who cites it
26 citing papers in PubMed.
- Drug Proarrhythmic Evaluation in a High Throughput Cardiac New Approach Methodology.bioRxiv : the preprint server for biology · 2026Article
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- Discovery of a novel broad-spectrum inhibitor against influenza virus A.Virology journal · 2025Article
- Integrating Transcriptomic and Targeted New Approach Methodologies into a Tiered Framework for Chemical Bioactivity Screening.Environmental health perspectives · 2025Article
- Bridging the Gap Between hiPSC-CMs Cardiotoxicity Assessment and Clinical LVEF Decline Risk: A Case Study of 21 Tyrosine Kinase Inhibitors.Pharmaceuticals (Basel, Switzerland) · 2025Article
- The differentiation state of small intestinal organoid models influences prediction of drug-induced toxicity.Frontiers in cell and developmental biology · 2025Article
- Harnessing large language models' zero-shot and few-shot learning capabilities for regulatory research.Briefings in bioinformatics · 2024Article
- Structural modeling of hERG channel-drug interactions using Rosetta.Frontiers in pharmacology · 2023Article
- Optimization of TAM16, a Benzofuran That Inhibits the Thioesterase Activity of Pks13; Evaluation toward a Preclinical Candidate for a Novel Antituberculosis Clinical Target.Journal of medicinal chemistry · 2022Article
- Cross clinical-experimental-computational qualification ofFrontiers in toxicology · 2022Article
- Article
- Ventricular voltage-gated ion channels: Detection, characteristics, mechanisms, and drug safety evaluation.Clinical and translational medicine · 2021Review
- Mechanisms of flecainide induced negative inotropy: An in silico study.Journal of molecular and cellular cardiology · 2021Article
- Update on ICH E14/S7B Cardiac Safety Regulations: The Expanded Role of Preclinical Assays and the "Double-Negative" Scenario.Clinical pharmacology in drug development · 2021Review
- Molecular determinants of pro-arrhythmia proclivity of d- and l-sotalol via a multi-scale modeling pipeline.Journal of molecular and cellular cardiology · 2021Article
- Optimization of the Urea Linker of Triazolopyridazine MMV665917 Results in a New Anticryptosporidial Lead with Improved Potency and Predicted hERG Safety Margin.Journal of medicinal chemistry · 2021Article
- Genetic and Molecular Aspects of Drug-Induced QT Interval Prolongation.International journal of molecular sciences · 2021Review
- Comprehensive in vitro pro-arrhythmic assays demonstrate that omecamtiv mecarbil has low pro-arrhythmic risk.Clinical and translational science · 2021Article
- Computational and experimental studies on the inhibitory mechanism of hydroxychloroquine on hERG.Toxicology · 2021Article
Corrections and comments
- Erratum issued
Authors and funding
43 authors.
Funding
Abstract
introductionhERG block potency is widely used to calculate a drug's safety margin against its torsadogenic potential. Previous studies are confounded by use of different patch clamp electrophysiology protocols and a lack of statistical quantification of experimental variability. Since the new cardiac safety paradigm being discussed by the International Council for Harmonisation promotes a tighter integration of nonclinical and clinical data for torsadogenic risk assessment, a more systematic approach to estimate the hERG block potency and safety margin is needed.
methodsA cross-industry study was performed to collect hERG data on 28 drugs with known torsadogenic risk using a standardized experimental protocol. A Bayesian hierarchical modeling (BHM) approach was used to assess the hERG block potency of these drugs by quantifying both the inter-site and intra-site variability. A modeling and simulation study was also done to evaluate protocol-dependent changes in hERG potency estimates.
resultsA systematic approach to estimate hERG block potency is established. The impact of choosing a safety margin threshold on torsadogenic risk evaluation is explored based on the posterior distributions of hERG potency estimated by this method. The modeling and simulation results suggest any potency estimate is specific to the protocol used. DISCUSSION: This methodology can estimate hERG block potency specific to a given voltage protocol. The relationship between safety margin thresholds and torsadogenic risk predictivity suggests the threshold should be tailored to each specific context of use, and safety margin evaluation may need to be integrated with other information to form a more comprehensive risk assessment.
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