Development of in-silico drug cardiac toxicity evaluation system with consideration of inter-individual variabilityopen access
- Authors
- Qauli, Ali Ikhsanul; Danadibrata, Rakha Zharfarizqi; Marcellinus, Aroli; Lim, Ki Moo
- Issue Date
- Jun-2024
- Publisher
- KSCPT
- Keywords
- Torsades de Pointes; In silico Simulation; Drug Toxicity; Inter-Individual Biological Variation
- Citation
- TRANSLATIONAL AND CLINICAL PHARMACOLOGY, v.32, no.2, pp 83 - 97
- Pages
- 15
- Journal Title
- TRANSLATIONAL AND CLINICAL PHARMACOLOGY
- Volume
- 32
- Number
- 2
- Start Page
- 83
- End Page
- 97
- URI
- https://scholarworks.bwise.kr/kumoh/handle/2020.sw.kumoh/28798
- DOI
- 10.12793/tcp.2024.32.e7
- ISSN
- 2289-0882
2383-5427
- Abstract
- Safety pharmacology examines the potential for new drugs to have unusual, rare side effects such as torsade de pointes (TdP). Recently, as a part of the Comprehensive in vitro Proarrhythmia Assay (CiPA) project, techniques for predicting the development of druginduced TdP through computer simulations have been proposed and verified. However, CiPA assessment generally does not consider the effect of cardiac cell inter-individual variability, especially related to metabolic status. The study aimed to explore whether rare proarrhythmic effects may be linked to the inter-individual variability of cardiac cells and whether incorporating this variability into computational models could alter the prediction of drugs' TdP risks. This study evaluated the contribution of two biological characteristics to the proarrhythmic effects. The first was spermine concentration, which varies with metabolic status; the second was L-type calcium permeability that could occur due to mutations. Twenty-eight drugs were examined throughout this study, and qNet was analyzed as an essential feature. Even though there were some discrepancies of TdP risk predictions from the baseline model, we found that considering the inter-individual variability might change the TdP risk of drugs. Several drugs in the high-risk drugs group were predicted to affect as intermediate and low-risk drugs in some individuals and vice versa. Also, most intermediaterisk drugs were expected to act as low-risk drugs. When compared, the effects of interindividual variability of L-type calcium were more significant than spermine in altering the TdP risk of compounds. These results emphasize the importance of considering interindividual variability to assess drugs.
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