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

Figure 1. The overall procedure for obtaining the predictions of TdP risk distribution under the effect of inter-individual variability. First, the simulations of drugs’ effects on the baseline models were utilized to generate the qNet thresholds. Second, the inter-individual variability simulations on 11×11 variations of spermine and L-type calcium permeability revealed the qNet map showing the distribution of TdP risk of drugs. Then the qNet thresholds would be used to separate three TdP regions on each qNet map. Furthermore, the 1,000 models were generated by varying the spermine and L-type calcium channels’ permeability using the log-normal distribution. The 1,000 models were filtered to fit the region of qNet map to obtain 880 models. From the 880 models, the corresponding qNet values were interpolated from the qNet map and the predicted distribution of TdP risk under inter-individual variability could be obtained as shown in Fig. 7. TdP, torsade de pointes.

Figure 2. Distribution of qNet values for drugs of training drugs. The red horizontal line represents qNet value distribution of high-risk drug group, the blue horizontal line represents qNet value distribution of intermediate-risk drug group, and the black horizontal line represents qNet value distribution of low-risk drug group. The cyan vertical line shows threshold1, and the red vertical line shows threshold2.

Figure 3. qNet map with the inter-individual variability applied for high-risk drugs group; y-axis represents the variation of permeability of L-type calcium ion channel, and x-axis shows the variation of spermine concentration in the individuals. The yellow-dashed line on x- and y-axis represent the default value of spermine concentration and calcium permeability from [21]. The colour represents the qNet value. The Th1-line shows the threshold1 value, and the Th2-line shows the threshold2 value.

Figure 4. qNet distribution with the inter-individual variability applied for intermediate-risk drugs group.

Figure 5. qNet distribution with the inter-individual variability applied for the low-risk drugs group.

Figure 6. Distribution of TdP risk prediction among individuals under high-risk drugs group (panel A), intermediate-risk group (panel B), and low-risk group (panel C). The colour represents the predicted TdP risk, i.e. red for high-risk, blue for intermediate risk, and green for low-risk. TdP, torsade de pointes.

Figure 7. Summary of TdP risk prediction with the inter-individual variability. The y-axis represents the share of the population (in percentage) on the particular predicted TdP class, the x-axis represents the initial TdP label of the drug, and the colour represents the predicted TdP class (red for high risk, blue for intermediate risk, and green for low risk). In a single-box plot, the lower, middle, and upper lines of the box represent the first quartile, median, and third quartile, respectively; the cross-line represents the average value; the circles represent outliers; the lower and upper lines outside the box represent the minimum and maximum values excluding the outliers. Note that the share of the population within predicted TdP risk is obtained by considering all drugs (28 drugs) from the same initial TdP label. TdP, torsade de pointes.