Windley, Monique J and Abi-Gerges, Najah and Fermini, Bernard and Hancox, Jules C and Vandenberg, Jamie I and Hill, Adam P (2017) Measuring kinetics and potency of hERG block for CiPA. Journal of Pharmacological and Toxicological Methods, 87. pp.99-107. ISSN 1873-488X (PP OA)
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Abstract
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 Channel Working Group was 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 ~500ms and ~15s. Seven drugs, however had time courses of block faster than this cut-off.
DISCUSSION
Here we describe the implementation of the standardized protocol for measurement 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.
| Item Type: | Article |
|---|---|
| Subjects: | R Medicine > R Medicine (General) |
| Depositing User: | Repository Administrator |
| Date Deposited: | 15 Feb 2017 03:17 |
| Last Modified: | 16 Jan 2018 00:22 |
| URI: | https://eprints.victorchang.edu.au/id/eprint/546 |
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