By Steve Jenkinson, VP Drug Discovery and Safety Assessment, Metrion
The recent ICH E14/S7B Q&As have provided much-needed clarity on the methodologies to be employed during GLP hERG testing in support of an IND filing for novel clinical compounds. A key recommendation is the use of three reference compounds - dofetilide, ondansetron, and moxifloxacin - to validate studies where data may be required for a Thorough QT (TQT) waiver application. This blog highlights a paper co-authored by Metrion that explores these themes, providing valuable insights into hERG IC50 values and safety margins across multiple laboratories.
Good Laboratory Practice (GLP) hERG testing has become an essential component of modern drug discovery. By ensuring that hERG testing is conducted to the highest standards, researchers can better predict the risk of drug-induced cardiac arrhythmias early in the development process. The recent ICH E14/S7B Q&As offer enhanced guidance on how these studies should be designed, including the use of the reference compounds dofetilide, ondansetron, and moxifloxacin. These compounds serve as benchmarks for evaluating the hERG inhibitory potency of new chemical entities, ensuring that safety margins are robust and reliable.
The publication, co-authored by Metrion and featured in the Journal of Pharmacological and Toxicological Methods, demonstrates how adhering to these best practices provides consistency and transparency in data - a vital factor when supporting an IND filing. Such rigour in GLP hERG testing directly impacts the safety profile assessments that underpin drug discovery programmes.
Central to the study is the evaluation of hERG IC50 values, which represent the concentration of a compound required to inhibit 50% of hERG channel activity. The paper presents a comprehensive analysis of 12 hERG IC50 datasets. This includes data from a single laboratory (comprising 5 datasets) and additional data from 6 other laboratories (totalling 7 datasets). The high degree of concordance in hERG IC50 values, both within and between laboratories, underscores the reliability of the GLP hERG testing protocols as prescribed by the ICH E14/S7B guidelines.
Moreover, the study utilised the inter-drug differences in potency to assess pooled margin variability. This approach has provided a robust reference for hERG safety margins, which are critical in integrated risk assessments during drug discovery. The findings support the use of a 30-fold safety margin as part of a comprehensive risk evaluation, though in situations where no additional assessment has been made, a more conservative 100-fold margin may be warranted.
The paper highlighted in this blog serves as an important milestone in the field of GLP hERG testing and drug discovery. By meticulously analysing hERG IC50 values across multiple laboratories, the study confirms that the use of reference compounds and adherence to ICH E14/S7B best practices result in highly consistent and reliable data. This, in turn, underpins the development of robust safety margins that are critical for the progression of new compounds through the drug discovery pipeline.
For those involved in drug discovery, the study offers reassurance that when GLP hERG testing is conducted according to the latest guidelines, the resulting data can be confidently used to support integrated risk assessments. This not only enhances the safety profile of novel clinical compounds but also streamlines the process of regulatory submission.
Leishman, D. J., Brimecombe, J., Crumb, W., Hebeisen, S., Jenkinson, S., Kilfoil, P. J., Matsukawa, H., Melliti, K., & Qu, Y. (2024). 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, 128, 107524. ISSN 1056-8719. https://doi.org/10.1016/j.vascn.2024.107524
By Steve Jenkinson, VP Drug Discovery and Safety Assessment, Metrion
The recent ICH E14/S7B Q&As have provided much-needed clarity on the methodologies to be employed during GLP hERG testing in support of an IND filing for novel clinical compounds. A key recommendation is the use of three reference compounds - dofetilide, ondansetron, and moxifloxacin - to validate studies where data may be required for a Thorough QT (TQT) waiver application. This blog highlights a paper co-authored by Metrion that explores these themes, providing valuable insights into hERG IC50 values and safety margins across multiple laboratories.
Good Laboratory Practice (GLP) hERG testing has become an essential component of modern drug discovery. By ensuring that hERG testing is conducted to the highest standards, researchers can better predict the risk of drug-induced cardiac arrhythmias early in the development process. The recent ICH E14/S7B Q&As offer enhanced guidance on how these studies should be designed, including the use of the reference compounds dofetilide, ondansetron, and moxifloxacin. These compounds serve as benchmarks for evaluating the hERG inhibitory potency of new chemical entities, ensuring that safety margins are robust and reliable.
The publication, co-authored by Metrion and featured in the Journal of Pharmacological and Toxicological Methods, demonstrates how adhering to these best practices provides consistency and transparency in data - a vital factor when supporting an IND filing. Such rigour in GLP hERG testing directly impacts the safety profile assessments that underpin drug discovery programmes.
Central to the study is the evaluation of hERG IC50 values, which represent the concentration of a compound required to inhibit 50% of hERG channel activity. The paper presents a comprehensive analysis of 12 hERG IC50 datasets. This includes data from a single laboratory (comprising 5 datasets) and additional data from 6 other laboratories (totalling 7 datasets). The high degree of concordance in hERG IC50 values, both within and between laboratories, underscores the reliability of the GLP hERG testing protocols as prescribed by the ICH E14/S7B guidelines.
Moreover, the study utilised the inter-drug differences in potency to assess pooled margin variability. This approach has provided a robust reference for hERG safety margins, which are critical in integrated risk assessments during drug discovery. The findings support the use of a 30-fold safety margin as part of a comprehensive risk evaluation, though in situations where no additional assessment has been made, a more conservative 100-fold margin may be warranted.
The paper highlighted in this blog serves as an important milestone in the field of GLP hERG testing and drug discovery. By meticulously analysing hERG IC50 values across multiple laboratories, the study confirms that the use of reference compounds and adherence to ICH E14/S7B best practices result in highly consistent and reliable data. This, in turn, underpins the development of robust safety margins that are critical for the progression of new compounds through the drug discovery pipeline.
For those involved in drug discovery, the study offers reassurance that when GLP hERG testing is conducted according to the latest guidelines, the resulting data can be confidently used to support integrated risk assessments. This not only enhances the safety profile of novel clinical compounds but also streamlines the process of regulatory submission.
Leishman, D. J., Brimecombe, J., Crumb, W., Hebeisen, S., Jenkinson, S., Kilfoil, P. J., Matsukawa, H., Melliti, K., & Qu, Y. (2024). 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, 128, 107524. ISSN 1056-8719. https://doi.org/10.1016/j.vascn.2024.107524
By Steve Jenkinson, VP Drug Discovery and Safety Assessment, Metrion
The recent ICH E14/S7B Q&As have provided much-needed clarity on the methodologies to be employed during GLP hERG testing in support of an IND filing for novel clinical compounds. A key recommendation is the use of three reference compounds - dofetilide, ondansetron, and moxifloxacin - to validate studies where data may be required for a Thorough QT (TQT) waiver application. This blog highlights a paper co-authored by Metrion that explores these themes, providing valuable insights into hERG IC50 values and safety margins across multiple laboratories.
Good Laboratory Practice (GLP) hERG testing has become an essential component of modern drug discovery. By ensuring that hERG testing is conducted to the highest standards, researchers can better predict the risk of drug-induced cardiac arrhythmias early in the development process. The recent ICH E14/S7B Q&As offer enhanced guidance on how these studies should be designed, including the use of the reference compounds dofetilide, ondansetron, and moxifloxacin. These compounds serve as benchmarks for evaluating the hERG inhibitory potency of new chemical entities, ensuring that safety margins are robust and reliable.
The publication, co-authored by Metrion and featured in the Journal of Pharmacological and Toxicological Methods, demonstrates how adhering to these best practices provides consistency and transparency in data - a vital factor when supporting an IND filing. Such rigour in GLP hERG testing directly impacts the safety profile assessments that underpin drug discovery programmes.
Central to the study is the evaluation of hERG IC50 values, which represent the concentration of a compound required to inhibit 50% of hERG channel activity. The paper presents a comprehensive analysis of 12 hERG IC50 datasets. This includes data from a single laboratory (comprising 5 datasets) and additional data from 6 other laboratories (totalling 7 datasets). The high degree of concordance in hERG IC50 values, both within and between laboratories, underscores the reliability of the GLP hERG testing protocols as prescribed by the ICH E14/S7B guidelines.
Moreover, the study utilised the inter-drug differences in potency to assess pooled margin variability. This approach has provided a robust reference for hERG safety margins, which are critical in integrated risk assessments during drug discovery. The findings support the use of a 30-fold safety margin as part of a comprehensive risk evaluation, though in situations where no additional assessment has been made, a more conservative 100-fold margin may be warranted.
The paper highlighted in this blog serves as an important milestone in the field of GLP hERG testing and drug discovery. By meticulously analysing hERG IC50 values across multiple laboratories, the study confirms that the use of reference compounds and adherence to ICH E14/S7B best practices result in highly consistent and reliable data. This, in turn, underpins the development of robust safety margins that are critical for the progression of new compounds through the drug discovery pipeline.
For those involved in drug discovery, the study offers reassurance that when GLP hERG testing is conducted according to the latest guidelines, the resulting data can be confidently used to support integrated risk assessments. This not only enhances the safety profile of novel clinical compounds but also streamlines the process of regulatory submission.
Leishman, D. J., Brimecombe, J., Crumb, W., Hebeisen, S., Jenkinson, S., Kilfoil, P. J., Matsukawa, H., Melliti, K., & Qu, Y. (2024). 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, 128, 107524. ISSN 1056-8719. https://doi.org/10.1016/j.vascn.2024.107524