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Following the 3 R's principles of animal research-replacement, reduction, and refinement-a high-performance computational framework was produced to generate a platform to perform human cardiac in-silico clinical trials as means to assess the pro-arrhythmic risk after the administrations of one or combination of two potentially arrhythmic drugs. The drugs assessed in this study were hydroxychloroquine and azithromycin. The framework employs electrophysiology simulations on high-resolution three-dimensional, biventricular human heart anatomies including phenotypic variabilities, so as to determine if differential QT-prolongation responds to drugs as observed clinically. These simulations also reproduce sex-specific ionic channel characteristics. The derived changes in the pseudo-electrocardiograms, calcium concentrations, as well as activation patterns within 3D geometries were evaluated for signs of induced arrhythmia. The virtual subjects could be evaluated at two different cycle lengths: at a normal heart rate and at a heart rate associated with stress as means to analyze the proarrhythmic risks after the administrations of hydroxychloroquine and azithromycin. Additionally, a series of experiments performed on reanimated swine hearts utilizing Visible Heart ® methodologies in a four-chamber working heart model were performed to verify the arrhythmic behaviors observed in the in silico trials.The obtained results indicated similar pro-arrhythmic risk assessments within the virtual population as compared to published clinical trials (21% clinical risk vs 21.8% in silico trial risk). Evidence of transmurally heterogeneous action potential prolongations after providing a large dose of hydroxychloroquine was found as the observed mechanisms for elicited arrhythmias, both in the in vitro and the in silico models. The proposed workflow for in silico clinical drug cardiotoxicity trials allows for reproducing the complex behavior of cardiac electrophysiology in a varied population, in a matter of a few days as compared to the months or years it requires for most in vivo human clinical trials. Importantly, our results provided evidence of the common phenotype variants that produce distinct drug-induced arrhythmogenic outcomes., (© 2024. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)