{"title":"hERG 抑制与 QTc 延长程度之间的关系:从体外到临床的转化分析","authors":"Alexander R. Harmer , Michael G. Rolf","doi":"10.1016/j.taap.2024.117135","DOIUrl":null,"url":null,"abstract":"<div><div>Assessing the magnitude of QTc prolongation is crucial in drug development due to its association with Torsades de Pointes. Inhibition of the hERG channel, pivotal in cardiac repolarization, is a key factor in evaluating this risk. In this study, the relationship between hERG inhibition and QTc prolongation magnitude was investigated, with the aim to derive simple guidance on the required hERG margin to avoid a large (>20 ms) QTc prolongation.</div></div><div><h3>Methods</h3><div>Data from literature and FDA sources were searched for compounds with hERG IC<sub>50</sub> values alongside clinical QTc data with paired plasma concentrations, or compounds demonstrating a clinical concentration-QTc relationship. Relationships between hERG inhibition, hERG IC<sub>50</sub> margin to unbound plasma C<sub>max</sub>, and QTc prolongation magnitude were calculated.</div></div><div><h3>Results</h3><div>Analysis of 148 clinical QTc observations from 98 compounds revealed that compounds associated with QTc prolongation >10 ms typically exhibited hERG margins of ≤33-fold, while those exceeding 20 ms were generally associated with margins of ≤24-fold. QTc increases above 10 ms were not observed at hERG margins >100-fold. Based on 53 clinical concentration-QTc datasets, modest hERG inhibition levels of <strong>∼</strong>4–6 % correlated with a 10 ms QTc prolongation, while <strong>∼</strong>10–13 % inhibition corresponded to a 20 ms prolongation.</div></div><div><h3>Conclusions</h3><div>This study enhances understanding of the relationship between hERG inhibition and QTc prolongation magnitude, by conducting analysis across a wide range of 98 compounds. This information can be used to determine the optimal hERG margin, particularly for drug discovery projects with limited scope to completely design-out hERG activity.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"492 ","pages":"Article 117135"},"PeriodicalIF":3.3000,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"On the relationship between hERG inhibition and the magnitude of QTc prolongation: An in vitro to clinical translational analysis\",\"authors\":\"Alexander R. Harmer , Michael G. Rolf\",\"doi\":\"10.1016/j.taap.2024.117135\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><div>Assessing the magnitude of QTc prolongation is crucial in drug development due to its association with Torsades de Pointes. Inhibition of the hERG channel, pivotal in cardiac repolarization, is a key factor in evaluating this risk. In this study, the relationship between hERG inhibition and QTc prolongation magnitude was investigated, with the aim to derive simple guidance on the required hERG margin to avoid a large (>20 ms) QTc prolongation.</div></div><div><h3>Methods</h3><div>Data from literature and FDA sources were searched for compounds with hERG IC<sub>50</sub> values alongside clinical QTc data with paired plasma concentrations, or compounds demonstrating a clinical concentration-QTc relationship. Relationships between hERG inhibition, hERG IC<sub>50</sub> margin to unbound plasma C<sub>max</sub>, and QTc prolongation magnitude were calculated.</div></div><div><h3>Results</h3><div>Analysis of 148 clinical QTc observations from 98 compounds revealed that compounds associated with QTc prolongation >10 ms typically exhibited hERG margins of ≤33-fold, while those exceeding 20 ms were generally associated with margins of ≤24-fold. QTc increases above 10 ms were not observed at hERG margins >100-fold. Based on 53 clinical concentration-QTc datasets, modest hERG inhibition levels of <strong>∼</strong>4–6 % correlated with a 10 ms QTc prolongation, while <strong>∼</strong>10–13 % inhibition corresponded to a 20 ms prolongation.</div></div><div><h3>Conclusions</h3><div>This study enhances understanding of the relationship between hERG inhibition and QTc prolongation magnitude, by conducting analysis across a wide range of 98 compounds. This information can be used to determine the optimal hERG margin, particularly for drug discovery projects with limited scope to completely design-out hERG activity.</div></div>\",\"PeriodicalId\":23174,\"journal\":{\"name\":\"Toxicology and applied pharmacology\",\"volume\":\"492 \",\"pages\":\"Article 117135\"},\"PeriodicalIF\":3.3000,\"publicationDate\":\"2024-11-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Toxicology and applied pharmacology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S0041008X2400334X\",\"RegionNum\":3,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"PHARMACOLOGY & PHARMACY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Toxicology and applied pharmacology","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0041008X2400334X","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"PHARMACOLOGY & PHARMACY","Score":null,"Total":0}
On the relationship between hERG inhibition and the magnitude of QTc prolongation: An in vitro to clinical translational analysis
Assessing the magnitude of QTc prolongation is crucial in drug development due to its association with Torsades de Pointes. Inhibition of the hERG channel, pivotal in cardiac repolarization, is a key factor in evaluating this risk. In this study, the relationship between hERG inhibition and QTc prolongation magnitude was investigated, with the aim to derive simple guidance on the required hERG margin to avoid a large (>20 ms) QTc prolongation.
Methods
Data from literature and FDA sources were searched for compounds with hERG IC50 values alongside clinical QTc data with paired plasma concentrations, or compounds demonstrating a clinical concentration-QTc relationship. Relationships between hERG inhibition, hERG IC50 margin to unbound plasma Cmax, and QTc prolongation magnitude were calculated.
Results
Analysis of 148 clinical QTc observations from 98 compounds revealed that compounds associated with QTc prolongation >10 ms typically exhibited hERG margins of ≤33-fold, while those exceeding 20 ms were generally associated with margins of ≤24-fold. QTc increases above 10 ms were not observed at hERG margins >100-fold. Based on 53 clinical concentration-QTc datasets, modest hERG inhibition levels of ∼4–6 % correlated with a 10 ms QTc prolongation, while ∼10–13 % inhibition corresponded to a 20 ms prolongation.
Conclusions
This study enhances understanding of the relationship between hERG inhibition and QTc prolongation magnitude, by conducting analysis across a wide range of 98 compounds. This information can be used to determine the optimal hERG margin, particularly for drug discovery projects with limited scope to completely design-out hERG activity.
期刊介绍:
Toxicology and Applied Pharmacology publishes original scientific research of relevance to animals or humans pertaining to the action of chemicals, drugs, or chemically-defined natural products.
Regular articles address mechanistic approaches to physiological, pharmacologic, biochemical, cellular, or molecular understanding of toxicologic/pathologic lesions and to methods used to describe these responses. Safety Science articles address outstanding state-of-the-art preclinical and human translational characterization of drug and chemical safety employing cutting-edge science. Highly significant Regulatory Safety Science articles will also be considered in this category. Papers concerned with alternatives to the use of experimental animals are encouraged.
Short articles report on high impact studies of broad interest to readers of TAAP that would benefit from rapid publication. These articles should contain no more than a combined total of four figures and tables. Authors should include in their cover letter the justification for consideration of their manuscript as a short article.