Personalized

Introduction: Drug-induced cardiotoxicity remains a leading cause of drug development failures and market withdrawals. Despite advances in preclinical testing, current Methods: We simulated concentration-dependent effects of amiodarone across combinations of hERG and Nav1.5 alleles in five human cardiac cell types: endocardial, epicardial, midwall, Purkinje, and atrial cells. APD90 values were evaluated across all cell types, whereas qNet was calculated in ventricular cells only to assess genotype and cell type dependent differences in electrophysiological response and torsadogenic risk. Results: Our results highlight how genetic variations and cell type context influence electrophysiological response to amiodarone, uncovering high-risk profiles otherwise masked in population-averaged models. These simulations reveal key insights with translational and regulatory relevance: genetic background meaningfully alters drug response; midmyocardial cells are disproportionately vulnerable; the same mutation can produce different effects across cell types; Purkinje cells may serve as silent proarrhythmic substrates; and celltype- specific differences in APD90 and qNet may provide additional insight beyond APD prolongation alone, and consequently improve prediction of torsades de pointes risk. Conclusion: Our work provides a foundation for the creation of digital twin models that incorporate patient-specific electrophysiology, offering a scalable platform for