BACKGROUND AND PURPOSE The advanced human induced pluripotent stem cell-derived cardiomyocyte (hiPSC-CMs) technology provides a novel in vitro platform for identification of the patients at high risk of drug-induced cardiotoxicity. Purpose of the current study is to develop an in vitro to in vivo translational platform to predict the incidence of drug induced cardiac dysfunction in clinic with hiPSC-CMs based in vitro assessment. EXPERIMENTAL APPROACH Doxorubicin induced cardiotoxicity was tested in hiPSC-CMs with varied exposure levels and durations. A mechanistic toxicodynamic (TD) model was developed to describe the concentration-response relationship of doxorubicin induced contraction magnitude reduction. The TD model was then integrated into a previous developed QSP-PBPK-TD model to generate an in vitro to in vivo translational platform. Virtual clinical trials were conducted to predict the clinical incidence of doxorubicin-induced cardiotoxicity in sub-populations with different drug exposures, susceptibility of cardiomyocytes, or cardiovascular disease statuses. KEY RESULTS The developed TD model successfully captured the concentration-response relationship and identified the mechanism of doxorubicin induced cardiotoxicity. The full-scale in vitro to in vivo QSP-PBPK-TD translational platform accurately predicted the reduction of left ventricular ejection fraction (LVEF) in patients with different myocardial susceptibilities or accepting different doxorubicin dosing schedules. A recommended dose table has been generated for individualized dosing of doxorubicin based on patient-specific hiPSC-CMs readouts. CONCLUSION AND IMPLICATIONS A QSP-PBPK-TD model-based in vitro to in vivo translational platform incorporating hiPSC-CMs-based in vitro testing has been developed to predict drug-induced cardiotoxicity. This platform could potentially improve accuracy of safe dose prediction for individual patients.