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Qauli, AI, Marcellinus, A, Vanheusden, FJ 
ORCID: https://orcid.org/0000-0003-2369-6189 and Lim, KM,
2024.
Cardiotoxicity evaluation of two-drug fixed-dose combination therapy under CiPA: a computational study.
Translational and Clinical Pharmacology, 32 (4), pp. 198-215.
ISSN 2289-0882
Abstract
The Comprehensive In Vitro Proarrhythmia Assay (CiPA) evaluates drug-induced torsade de pointes (TdP) risk, with qNet commonly used to classify drugs into low-, intermediate-, and high-risk categories. While most studies focus on single-drug effects, 2-drug fixed-dose combination (FDC) therapy is widely used for cardiovascular disease management. We aimed to develop the CiPA-based methodology to predict adverse effects of FDC therapy. A human ventricular cell model was stimulated under the effects of various drug combinations from twelve well-characterized compounds suggested by CiPA at 1 to 4 maximum plasma concentration, and the qNetavg biomarker as a function of the ratio of two drugs was used to evaluate the TdP risk of combined compounds. Results showed that high-risk and intermediate-risk drug combinations often yielded lower qNetavg than individual drugs, suggesting increased TdP risk. Conversely, combinations involving low-risk drugs tended to reduce TdP risk by raising qNetavg above individual drug levels. Also, we found that the interplay of some major ionic channels caused variations on qNetavg. These findings highlight the importance of evaluating FDC cardiotoxicity to predict risks that may not appear in single-drug analysis.
| Item Type: | Journal article |
|---|---|
| Publication Title: | Translational and Clinical Pharmacology |
| Creators: | Qauli, A.I., Marcellinus, A., Vanheusden, F.J. and Lim, K.M. |
| Publisher: | Korean Society for Clinical Pharmacology and Therapeutics |
| Date: | December 2024 |
| Volume: | 32 |
| Number: | 4 |
| ISSN: | 2289-0882 |
| Identifiers: | Number Type 10.12793/tcp.2024.32.e20 DOI 2342763 Other |
| Rights: | Creative Commons Attribution Non-Commercial License (https://creativecommons.org/licenses/by-nc/4.0/). |
| Divisions: | Schools > School of Science and Technology |
| Record created by: | Jonathan Gallacher |
| Date Added: | 15 Jan 2025 14:27 |
| Last Modified: | 15 Jan 2025 14:27 |
| URI: | https://irep.ntu.ac.uk/id/eprint/52853 |
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