Kilfoil, Peter, Feng, Shuyun Lily, Bassyouni, Asser, Lee, Tiffany, Leishman, Derek, Li, Dingzhou, MacEwan, David J 
ORCID: 0000-0002-2879-0935, Sharma, Parveen ORCID: 0000-0002-5534-2417, Watt, Eric D and Jenkinson, Stephen
(2021)
Characterization of a high throughput human stem cell cardiomyocyte assay to predict drug-induced changes in clinical electrocardiogram parameters.
European Journal of Pharmacology, 912.
p. 174584.
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Abstract
Human induced pluripotent stem cell derived cardiomyocytes (hIPSC-CM's) play an increasingly important role in the safety profiling of candidate drugs. For such models to have utility a clear understanding of clinical translation is required. In the present study we examined the ability of our hIPSC-CM model to predict the clinically observed effects of a diverse set of compounds on several electrocardiogram endpoints, including changes in QT and QRS intervals. To achieve this, compounds were profiled in a novel high throughput voltage-sensitive dye platform. Measurements were taken acutely (30 min) and chronically (24 h) to ensure that responses from compounds with slow onset kinetics or that affected surface ion channel expression would be captured. In addition, to avoid issues associated with changes in free drug levels due to protein binding, assays were run in serum free conditions. Changes in hIPSC-CM threshold APD<sub>90</sub> values correlated with compound plasma exposures that produced a +10 ms change in clinical QTc (Pearson r<sup>2</sup> = 0.80). In addition, randomForest modeling showed high predictivity in defining TdP risk (AUROC value = 0.938). Risk associated with QRS prolongation correlated with an increase in action potential rise-time (AUROC value = 0.982). The in-depth understanding of the clinical translatability of our hIPSC-CM model positions this assay to play a key role in defining cardiac risk early in drug development. Moreover, the ability to perform longer term studies enables the detection of compounds that may not be highlighted by more acute assay formats, such as inhibitors of hERG trafficking.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | Action potential, Clinical, QTc, Stem cell, Torsades de pointes |
| Divisions: | Faculty of Health and Life Sciences Faculty of Health and Life Sciences > Institute of Life Courses and Medical Sciences |
| Depositing User: | Symplectic Admin |
| Date Deposited: | 25 Oct 2021 08:43 |
| Last Modified: | 18 Jan 2023 21:25 |
| DOI: | 10.1016/j.ejphar.2021.174584 |
| Related URLs: | |
| URI: | https://livrepository.liverpool.ac.uk/id/eprint/3141575 |
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