Cardiotoxicity evaluation of two-drug fixed-dose combination therapy under CiPA: a computational study

Figures

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  Figure 1. Protocol for in-silico simulations of the effects of a single drug and FDC. (A) The single drug simulation. Drug information, including IC50 and Hill’s coefficient for seven ion channels, was used. Cell models were first stimulated 1,000 times drug-free, followed by 1,000 stimulations with the drug. The output was qNet values across several drug concentrations (1−4× cmax), and qNetavg was calculated. Ordinal logistic regression then classified drugs into low, intermediate, or high-risk groups based on qNetavg thresholds. (B) The FDC simulation. Inputs included IC50 and Hill’s coefficient for 2 drugs, with drug ratios adjusted by parameters (r and θ). The Bliss independence model was used, and qNetavg (θ) was calculated by averaging qNetavg (r,θ) across different r values. The qNetavg (θ) was used to assess TdP risk of the FDC based on qNetavg thresholds from the single drug simulations. Further details are provided in the methods section. FDC, fixed-dose combination.

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  Figure 2. qNetavg distribution for 12 CiPA drugs (single drug effects) is shown with color coding for TdP risk: red for high-risk, blue for intermediate-risk, and green for low-risk. The horizontal dashed lines represent qNetavg thresholds: red for threshold1=0.0521 µC/µF and blue for threshold2=0.0664 µC/µF. Samples with qNetavg below threshold1 were categorized as high-risk, between threshold1 and threshold2 as intermediate-risk, and above threshold2 as low-risk samples. CiPA, Comprehensive In Vitro Proarrhythmia Assay; TdP, torsade de pointes.

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  Figure 3. Drug combination plots for TdP risk predictions are shown for 66 possible combinations of 12 CiPA drugs. Each plot displays the variation of qNetavg (θ) for the combined compounds, with red, blue, and green areas representing TdP risk regions. The horizontal black dashed line indicates the drug-free simulation result (qNetavg=0.072 µC/µF). The black line represents the mean qNetavg (θ), while the transparent white region shows variations from 100 samples. TdP, torsade de pointes; CiPA, Comprehensive In Vitro Proarrhythmia Assay.