Development of in-silico drug cardiac toxicity evaluation system with consideration of inter-individual variability.

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 drug-induced 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 intermediate-risk drugs were expected to act as low-risk drugs. When compared, the effects of inter-individual variability of L-type calcium were more significant than spermine in altering the TdP risk of compounds. These results emphasize the importance of considering inter-individual variability to assess drugs.

Validation of in silico biomarkers for drug screening through ordinal logistic regression.

Since the Comprehensive in vitro Proarrhythmia Assay (CiPA) initiation, many studies have suggested various in silico features based on ionic charges, action potentials (AP), or intracellular calcium (Ca) to assess proarrhythmic risk. These in silico features are computed through electrophysiological simulations using in vitro experimental datasets as input, therefore changing with the quality of in vitro experimental data; however, research to validate the robustness of in silico features for proarrhythmic risk assessment of drugs depending on in vitro datasets has not been conducted. This study aims to verify the availability of in silico features commonly used in assessing the cardiac toxicity of drugs through an ordinal logistic regression model and three in vitro datasets measured under different experimental environments and with different purposes. We performed in silico drug simulations using the Tomek-Ohara Rudy (ToR-ORD) ventricular myocyte model and computed 12 in silico features comprising six AP features, four Ca features, and two ion charge features, which reflected the effect and characteristics of each in vitro data for CiPA 28 drugs. We then compared the classific performances of ordinal logistic regressions according to these 12 in silico features and used in vitro datasets to validate which in silico feature is the best for assessing the proarrhythmic risk of drugs at high, intermediate, and low levels. All 12 in silico features helped determine high-risky torsadogenic drugs, regardless of the in vitro datasets used in the in silico simulation as input. In the three types of in silico features, AP features were the most reliable for determining the three Torsade de Pointes (TdP) risk standards. Among AP features, AP duration at 50% repolarization (APD50) was the best when individually using in silico features per in vitro dataset. In contrast, the AP repolarization velocity (dVm/dtMax_repol) was the best when merging all in silico features computed through three in vitro datasets.