Windley, Monique J and Lee, William and Vandenberg, Jamie I and Hill, Adam P (2018) The temperature dependence of kinetics associated with drug block of hERG channels are compound specific and an important factor for proarrhythmic risk prediction. Molecular Pharmacology, 94 (1). pp.760-769. ISSN 1521-0111 (PP OA)
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Abstract
Current mandated preclinical tests for drug induced proarrhythmia are very sensitive, but not sufficiently specific. This has led to concern that there is a high attrition rate of potentially safe drugs that could have been beneficial to patients. The comprehensive in vitro pro-arrhythmia (CiPA) initiative has proposed new metrics based around in silico risk predictions, which are informed, amongst other things, by measures of hERG block kinetics. However, high throughput patch-clamp systems set to collect this data largely operate at ambient temperature, while the simulations for risk prediction are carried out at physiological temperature. The aims of this study were i) To determine to what degree kinetics of drug block of hERG are temperature dependent; ii) Assess the impact of any temperature dependence of drug binding kinetics on repolarization in silico; and iii) Identify whether a common set of Q10 scalars can be used to extrapolate kinetic data gathered at ambient to physiological temperatures for use in in silico proarrhythmic risk prediction. We show for a range of drugs that kinetics of block are temperature dependent and furthermore that the degree of temperature dependence is different for each drug. As a result, no common set of Q10 scalars could describe the observed range of temperature dependencies. These results suggest that if accurate physiological temperature models of the kinetics of drug binding are important for in silico risk prediction, the in vitro data should be acquired at physiological temperature.
| Item Type: | Article |
|---|---|
| Subjects: | R Medicine > R Medicine (General) |
| Depositing User: | Repository Administrator |
| Date Deposited: | 14 May 2018 03:09 |
| Last Modified: | 11 Mar 2019 04:42 |
| URI: | https://eprints.victorchang.edu.au/id/eprint/728 |
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