A systematic strategy for estimating hERG block potency and its implications in a new cardiac safety paradigm
Bradley J. Ridder, Derek J. Leishman, Matthew Bridgland‐Taylor, Mohammadreza Samieegohar, Xiaomei Han, Wendy Wu, Aaron Randolph, P. Tran, Jiansong Sheng, Timm Danker, Anders Lindqvist, Daniel Konrad, Simon Hebeisen, Liudmila Polonchuk, Evgenia Gissinger, Muthukrishnan Renganathan, Bryan Koci, Haiyang Wei, Jing‐Song Fan, Paul Lévesque, Jae Kwagh, John P. Imredy, Jin Zhai, Marc Rogers, Edward Humphries, Robert Kirby, Sonja Stoelzle‐Feix, Nina Brinkwirth, Maria Giustina Rotordam, Nadine Becker, Søren Friis, Markus Rapedius, Tom A. Goetze, Tim Strassmaier, George Okeyo, James Kramer, Yuri A. Kuryshev, Caiyun Wu, Herbert M. Himmel, Gary R. Mirams, David G. Strauss, Rémi Bardenet, Zhihua Li
Abstract
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.