Toxicology and applied pharmacology · 2024
On the relationship between hERG inhibition and the magnitude of QTc prolongation: An in vitro to clinical translational analysis.
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Harmer Alexander R, Rolf Michael G
Аннотация
UNLABELLED: 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.
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.