Measuring kinetics and potency of hERG block for CiPA

作者：Windley Monique J; Abi Gerges Najah; Fermini Bernard; Hancox Jules C; Vandenberg Jamie I; Hill Adam P^*

来源：Journal of Pharmacological and Toxicological Methods, 2017, 87: 99-107.

DOI：10.1016/j.vascn.2017.02.017

• Acquired long QT
• CiPA
• Drug screening
• hERG
• Proarrhythmic risk

Introduction: The Comprehensive in vitro Proarrhythmic Assay (CiPA) aims to update current cardiac safety testing to better evaluate arrhythmic risk. A central theme of CiPA is the use of in silico approaches to risk prediction incorporating models of drug binding to hERG. To parameterize these models, accurate in vitro measurement of potency and kinetics of block is required. The Ion ChannelWorking Groupwas tasked with: i) selecting a protocol that could measure kinetics of block and was easily implementable on automated platforms for future rollout in industry and ii) acquiring a reference dataset using the standardized protocol.
Methods: Data were acquired using a 'step depolarisation' protocol using manual patch-clamp at ambient temperature.
Results: Potency, kinetics and trapping characteristics of hERG block for the CiPA training panel of twelve drugs were measured. Timecourse of block and trapping characteristics could be reliably measured if the time constant for onset of block was between similar to 500 ms and similar to 15 s. Seven drugs, however had time courses of block faster than this cut-off. Discussion: Here we describe the implementation of the standardized protocol formeasurement of kinetics and potency of hERG block for CiPA. The results highlight the challenges in identifying a single protocol to measure hERG block over a range of kinetics. The dataset from this study is being used by the In Silico Working Group to develop models of drug binding for risk prediction and is freely available as a 'gold standard' ambient temperature dataset to evaluate variability across high throughput platforms.

• 出版日期2017-9