Validation and Clinical Utility of the <scp>hERG IC</scp>50:C<sub>max</sub> Ratio to Determine the Risk of Drug‐Induced Torsades de Pointes: A Meta‐Analysis

Lehmann, David F.; Eggleston, William; Wang, Dongliang

doi:10.1002/phar.2087

Cited by 26 publications

(17 citation statements)

References 33 publications

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“…On the other hand, several drugs in clinical use (among those are antihistamines, fluoroquinolone antibiotics, antipsychotics, antiepileptics) exert off-target inhibitory effects on hERG1 partially with submicromolar IC 50 s but are "non-torsadogenic." One might assume that clinically achieved steady state free plasma concentrations of these "non-torsadogenic" hERG1 inhibitors remain far below its IC 50 concentration for hERG1 (Lehmann et al, 2018). Another explanation for the "non-torsadogenicity" of these drugs is that hERG1 inhibition alone is not sufficient to induce fatal arrhythmia, and the "torsadogenic" action of a certain drug depends on the full spectrum of ion channels that is modulated by the drug [for commentary see (Arcangeli and Becchetti, 2017)].…”

Section: Discussionmentioning

confidence: 99%

hERG K+ Channels Promote Survival of Irradiated Leukemia Cells

et al. 2020

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Many tumor cells express highly elevated activities of voltage-gated K + channels in the plasma membrane which are indispensable for tumor growth. To test for K + channel function during DNA damage response, we subjected human chronic myeloid leukemia (CML) cells to sub-lethal doses of ionizing radiation (0-8 Gy, 6 MV photons) and determined K + channel activity, K + channel-dependent Ca 2+ signaling, cell cycle progression, DNA repair, and clonogenic survival by whole-cell patch clamp recording, fura-2 Ca 2+ imaging, Western blotting, flow cytometry, immunofluorescence microscopy, and pre-plating colony formation assay, respectively. As a result, the human erythroid CML cell line K562 and primary human CML cells functionally expressed hERG1. Irradiation stimulated in both cell types an increase in the activity of hERG1 K + channels which became apparent 1-2 h post-irradiation. This increase in K + channel activity was paralleled by an accumulation in S phase of cell cycle followed by a G 2 /M cell cycle arrest as analyzed between 8 and 72 h post-irradiation. Attenuating the K + channel function by applying the hERG1 channel inhibitor E4031 modulated Ca 2+ signaling, impaired inhibition of the mitosis promoting subunit cdc2, overrode cell cycle arrest, and decreased clonogenic survival of the irradiated cells but did not affect repair of DNA double strand breaks suggesting a critical role of the hERG1 K + channels for the Ca 2+ signaling and the cell cycle control during DNA damage response.

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Section: Discussionmentioning

confidence: 99%

hERG K+ Channels Promote Survival of Irradiated Leukemia Cells

et al. 2020

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“…[7][8][9][10] Highly selective binding for the D 2 receptors makes olanzapine an attractive option for patients in whom there is a concern for QT prolongation chosen due to its low binding affinity for the I kr channel. 19 In addition, in a meta-analysis to validate the clinical utility of the ratio of the half-maximum inhibition concentration of the hERG channel (hERG IC50) to the peak serum concentration of unbound drug (C max ), Lehmann et al 20 reported that olanzapine is the antipsychotic with the least risk of drug-induced torsade de pointes. Although olanzapine is only approved parenterally for IM use, evidence suggests that IV use may be safe.…”

Section: Discussionmentioning

confidence: 99%

Intravenous Olanzapine in a Critically Ill Patient: An Evolving Route of Administration

2019

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Purpose: The purpose of the article is to describe the successful use of parenteral olanzapine intravenously (IV) in a critically ill patient with severe agitated delirium. Summary: A 70-year-old man was admitted to the medical intensive care unit requiring plasmapheresis with platelet counts consistently below 20 000/µL secondary to thrombotic thrombocytopenic purpura (TTP). The patient had experienced agitated delirium requiring treatment, which was complicated by electrocardiogram (EKG) findings of a prolonged QTc interval. The antipsychotics the patient was receiving were believed to be responsible and, as such, the team desired an option that would have a lesser chance of worsening QTc (baseline-corrected QT) interval. Olanzapine was chosen and given IV versus the U.S. Food and Drug Administration (FDA)–approved parenteral route of intramuscular (IM) due to concern of bleeding. The patient’s delirious state responded to treatment to varying degrees and showed no increase in EKG abnormalities. To our knowledge, there is a paucity of published literature regarding this route of administration. Conclusion: Intramuscular olanzapine used IV may be a safe and effective option for the treatment of acutely agitated, delirious, critically ill patient.

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“…Since it is hard to determine the hERG liability of a drug based on the IC 50 value alone, 35 without the knowledge of the peak serum concentration unbound to plasma proteins, we use both activity thresholds (1M and 10 M) to classify the drugs as blockers and non-blockers. Recent progress in deep learning facilitates the development of the different molecular representations such as latent vectors that are used as descriptors for modeling molecular properties.…”

Section: Methodsmentioning

confidence: 99%

Critical Assessment of Artificial Intelligence Methods for Prediction of hERG Channel Inhibition in the “Big Data” Era

Siramshetty

Nguyễn

Martínez

et al. 2020

J. Chem. Inf. Model.

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The rise of novel artificial intelligence methods necessitates a comparison of this wave of new approaches with classical machine learning for a typical drug discovery project. Inhibition of the potassium ion channel, whose alpha subunit is encoded by human Ether-à-go-go-Related Gene (hERG), leads to prolonged QT interval of the cardiac action potential and is a significant safety pharmacology target for the development of new medicines. Several computational approaches have been employed to develop prediction models for assessment of hERG liabilities of small molecules including recent work using deep learning methods. Here we perform a comprehensive comparison of prediction models based on classical (random forests and gradient boosting) and modern (deep neural networks and recurrent neural networks) artificial intelligence methods. The training set (~9000 compounds) was compiled by integrating hERG bioactivity data from ChEMBL database with experimental data generated from an in-house, high-throughput thallium flux assay.We utilized different molecular descriptors including the latent descriptors, which are real-valued continuous vectors derived from chemical autoencoders trained on a large chemical space (> 1.5 million compounds).The models were prospectively validated on ~840 in-house compounds screened in the same thallium flux assay. The deep neural networks performed significantly better than the classical methods with the latent descriptors. The recurrent neural networks that operate on SMILES provided highest model sensitivity. The best models were merged into a consensus model that offered superior performance compared to reference models from academic and commercial domains. Further, we shed light on the potential of artificial intelligence methods to exploit the chemistry big data and generate novel chemical representations useful in predictive modeling and tailoring new chemical space. File list (2) download file view on ChemRxiv Critical Assessment of Artificial Intelligence Methods for Pr... (1.91 MiB) download file view on ChemRxiv Supporting Information.docx (495.71 KiB)

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Validation and Clinical Utility of the hERG IC50:C_max Ratio to Determine the Risk of Drug‐Induced Torsades de Pointes: A Meta‐Analysis

Abstract: The hERG IC50:C ratio was correlated with TdP incidence for culprit drugs. This validation provides support for the potential use of the hERG IC50:C ratio for clinical decision making in instances of drug selection where TdP risk is a concern.

Cited by 26 publications

References 33 publications

hERG K+ Channels Promote Survival of Irradiated Leukemia Cells

hERG K+ Channels Promote Survival of Irradiated Leukemia Cells

Intravenous Olanzapine in a Critically Ill Patient: An Evolving Route of Administration

Critical Assessment of Artificial Intelligence Methods for Prediction of hERG Channel Inhibition in the “Big Data” Era

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Validation and Clinical Utility of the hERG IC50:Cmax Ratio to Determine the Risk of Drug‐Induced Torsades de Pointes: A Meta‐Analysis

Abstract: The hERG IC50:C ratio was correlated with TdP incidence for culprit drugs. This validation provides support for the potential use of the hERG IC50:C ratio for clinical decision making in instances of drug selection where TdP risk is a concern.

Cited by 26 publications

References 33 publications

hERG K+ Channels Promote Survival of Irradiated Leukemia Cells

hERG K+ Channels Promote Survival of Irradiated Leukemia Cells

Intravenous Olanzapine in a Critically Ill Patient: An Evolving Route of Administration

Critical Assessment of Artificial Intelligence Methods for Prediction of hERG Channel Inhibition in the “Big Data” Era

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Validation and Clinical Utility of the hERG IC50:C_max Ratio to Determine the Risk of Drug‐Induced Torsades de Pointes: A Meta‐Analysis