A systematic strategy for estimating hERG block potency and its implications in a new cardiac safety paradigm

Bardenet, R�mi; Ridder, Bradley J.; Leishman, Derek J.; Bridgland-Taylor, Matthew; Samieegohar, Mohammadreza; Han, Xiaomei; Wu, Wendy W.; Randolph, Aaron; Tran, Phu; Sheng, Jiansong; Danker, Timm; Lindqvist, Anders; Konrad, Daniel; Hebeisen, Simon; Polonchuk, Liudmila; Gissinger, Evgenia; Renganathan, Muthukrishnan; Koci, Bryan; Wei, Haiyang; Fan, Jingsong; Levesque, Paul; Kwagh, Jae; Imredy, John; Zhai, Jin; Rogers, Marc; Humphries, Edward; Kirby, Robert; Stoelzle-Feix, Sonja; Brinkwirth, Nina; Rotordam, Maria Giustina; Becker, Nadine; Friis, S�ren; Rapedius, Markus; Goetze, Tom A.; Strassmaier, Tim; Okeyo, George; Kramer, James; Kuryshev, Yuri; Wu, Caiyun; Himmel, Herbert; Mirams, Gary R.; Strauss, David G.; Bardenet, Remi; Li, Zhihua

Abstract

© 2020 Introduction: hERG block potency is widely used to calculate a drug's safety margin against its torsadogenic potential. Previous studies are confounded by use of different patch clamp electrophysiology protocols and a lack of statistical quantification of experimental variability. Since the new cardiac safety paradigm being discussed by the International Council for Harmonisation promotes a tighter integration of nonclinical and clinical data for torsadogenic risk assessment, a more systematic approach to estimate the hERG block potency and safety margin is needed. Methods: A cross-industry study was performed to collect hERG data on 28 drugs with known torsadogenic risk using a standardized experimental protocol. A Bayesian hierarchical modeling (BHM) approach was used to assess the hERG block potency of these drugs by quantifying both the inter-site and intra-site variability. A modeling and simulation study was also done to evaluate protocol-dependent changes in hERG potency estimates. Results: A systematic approach to estimate hERG block potency is established. The impact of choosing a safety margin threshold on torsadogenic risk evaluation is explored based on the posterior distributions of hERG potency estimated by this method. The modeling and simulation results suggest any potency estimate is specific to the protocol used. Discussion: This methodology can estimate hERG block potency specific to a given voltage protocol. The relationship between safety margin thresholds and torsadogenic risk predictivity suggests the threshold should be tailored to each specific context of use, and safety margin evaluation may need to be integrated with other information to form a more comprehensive risk assessment.

Citation

Bardenet, R., Ridder, B. J., Leishman, D. J., Bridgland-Taylor, M., Samieegohar, M., Han, X., …Li, Z. (2020). A systematic strategy for estimating hERG block potency and its implications in a new cardiac safety paradigm. Toxicology and Applied Pharmacology, 394, Article 114961. https://doi.org/10.1016/j.taap.2020.114961

• Journal Article Type: Article
• Acceptance Date: Mar 19, 2020
• Online Publication Date: Mar 21, 2020
• Publication Date: May 1, 2020
• Deposit Date: May 31, 2020
• Publicly Available Date: Jun 1, 2020
• Journal: Toxicology and Applied Pharmacology
• Print ISSN: 0041-008X
• Electronic ISSN: 1096-0333
• Publisher: Elsevier
• Peer Reviewed: Peer Reviewed
• Volume: 394
• Article Number: 114961
• DOI: https://doi.org/10.1016/j.taap.2020.114961
• Keywords: Toxicology; Pharmacology
• Public URL: https://nottingham-repository.worktribe.com/output/4198126
• Publisher URL: https://www.sciencedirect.com/science/article/pii/S0041008X20300855?via%3Dihub