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A systematic strategy for estimating hERG block potency and its implications in a new cardiac safety paradigm.
Toxicology and Applied Pharmacology ( IF 3.3 ) Pub Date : 2020-03-21 , DOI: 10.1016/j.taap.2020.114961
Bradley J Ridder 1 , Derek J Leishman 2 , Matthew Bridgland-Taylor 3 , Mohammadreza Samieegohar 1 , Xiaomei Han 1 , Wendy W Wu 1 , Aaron Randolph 1 , Phu Tran 1 , Jiansong Sheng 4 , Timm Danker 5 , Anders Lindqvist 6 , Daniel Konrad 7 , Simon Hebeisen 7 , Liudmila Polonchuk 8 , Evgenia Gissinger 8 , Muthukrishnan Renganathan 9 , Bryan Koci 9 , Haiyang Wei 9 , Jingsong Fan 10 , Paul Levesque 10 , Jae Kwagh 10 , John Imredy 11 , Jin Zhai 11 , Marc Rogers 12 , Edward Humphries 12 , Robert Kirby 12 , Sonja Stoelzle-Feix 13 , Nina Brinkwirth 13 , Maria Giustina Rotordam 13 , Nadine Becker 13 , Søren Friis 13 , Markus Rapedius 13 , Tom A Goetze 13 , Tim Strassmaier 14 , George Okeyo 14 , James Kramer 15 , Yuri Kuryshev 15 , Caiyun Wu 15 , Herbert Himmel 16 , Gary R Mirams 17 , David G Strauss 1 , Rémi Bardenet 18 , Zhihua Li 1
Affiliation  

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.

中文翻译:

评估hERG阻滞效力的系统策略及其在新的心脏安全范例中的意义。

引言hERG阻滞效力被广泛用于计算药物对抗其致死性潜力的安全性。先前的研究由于使用不同的膜片钳电生理方案而混淆,并且缺乏对实验变异性的统计量化。由于国际协调委员会正在讨论的新的心脏安全范例促进了将非临床和临床数据更紧密地整合在一起,以进行致源性致病风险评估,因此需要一种更加系统的方法来评估hERG阻滞效力和安全性。方法采用标准化实验方案,进行了一项跨行业研究,以收集关于28种已知致癌风险的药物的hERG数据。贝叶斯分级建模(BHM)方法用于通过量化站点间和站点内的变异性来评估这些药物的hERG阻断效力。还进行了建模和仿真研究,以评估hERG效能估计中依赖协议的变化。结果建立了评估hERG阻断效力的系统方法。基于此方法估算的hERG效价的后验分布,探讨了选择安全裕度阈值对躯体致癌风险评估的影响。建模和仿真结果表明,任何效价估计都特定于所使用的协议。讨论这种方法可以估计特定于给定电压协议的hERG阻断效力。
更新日期:2020-03-22
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