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

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 qNet_avg 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 qNet_avg than individual drugs, suggesting increased TdP risk. Conversely, combinations involving low-risk drugs tended to reduce TdP risk by raising qNet_avg above individual drug levels. Also, we found that the interplay of some major ionic channels caused variations on qNet_avg. These findings highlight the importance of evaluating FDC cardiotoxicity to predict risks that may not appear in single-drug analysis.