By Steve Jenkinson, VP Drug Discovery and Safety Assessment, Metrion Biosciences
The recent ICH E14/S7B Q&As have provided more clarity on the methodologies that should be employed when conducting a GLP hERG to support and IND filing for a novel clinical compound. This includes the suggestion of three reference compounds (dofetilide, ondansetron and moxifloxacin) that may be used to validate a study where data may be required for use in a Thorough QT (TQT) waiver application.
In this current study GLP hERG data were generated for the three reference compounds using ICH best practices in order to understand intra and inter laboratory variability in the data and to assess a suitable hERG safety margin under these conditions. The analyses used 12 hERG IC50 with a group of 5 data sets from a single laboratory and an additional 7 data sets collected by 6 different laboratories. The data highlight the high degree of concordance of results with respect to both intra and inter laboratory variability with respect to hERG IC50 values. Moreover, the inter-drug differences in potency were used to determine pooled margin variability.
The combined data provided a robust hERG margin reference based on best practice guidelines and consistent exposure denominators (provided in the ICH E14/S7B Training Materials). The sensitivity of the hERG margin thresholds generated using the updated ICH best practices were consistent with the sensitivity described over the course of the last two decades. The data are supportive of using a safety of a 30-fold safety margin as part of a more comprehensive integrated risk assessment, although a more conservative 100-fold margin may be more appropriate where no additional assessment has been made.
Derek J. Leishman, Jessica Brimecombe, William Crumb, Simon Hebeisen, Steve Jenkinson, Peter J. Kilfoil, Hiroshi Matsukawa, Karim Melliti, Yusheng Qu, Supporting an integrated QTc risk assessment using the hERG margin distributions for three positive control agents derived from multiple laboratories and on multiple occasions., Journal of Pharmacological and Toxicological Methods, Volume 128, 2024, 107524, ISSN 1056-8719, https://doi.org/10.1016/j.vascn.2024.107524.
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