On the relationship between hERG inhibition and the magnitude of QTc prolongation: An in vitro to clinical translational analysis

IF 3.3 3区医学 Q2 PHARMACOLOGY & PHARMACY

Toxicology and applied pharmacology Pub Date : 2024-11-01 DOI:10.1016/j.taap.2024.117135

Alexander R. Harmer , Michael G. Rolf

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引用次数: 0

Abstract

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 C_max, 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.

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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

由于 QTc 延长与 Torsades de Pointes 有关，因此评估 QTc 延长的程度对药物开发至关重要。hERG 通道是心脏复极化的关键通道，抑制该通道是评估这种风险的关键因素。本研究调查了 hERG 抑制与 QTc 延长幅度之间的关系，目的是为避免出现较大（20 毫秒）的 QTc 延长所需的 hERG 余量提供简单的指导。结果分析了 98 种化合物的 148 次临床 QTc 观察结果，发现与 QTc 延长 >10 毫秒相关的化合物的 hERG 边际值通常≤33 倍，而超过 20 毫秒的化合物的边际值通常≤24 倍。在 hERG 差值为 100 倍时，未观察到 QTc 上升超过 10 毫秒的情况。基于 53 个临床浓度-QTc 数据集，4%-6% 的适度 hERG 抑制水平与 10 毫秒的 QTc 延长相关，而 10%-13% 的抑制水平则与 20 毫秒的 QTc 延长相对应。这些信息可用于确定最佳的 hERG 余量，特别是对于完全设计出 hERG 活性的范围有限的药物发现项目。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Toxicology and applied pharmacology 医学-毒理学

CiteScore

6.80

自引率

2.60%

发文量

309

审稿时长

32 days

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.