An In Silico Platform to Predict Cardiotoxicity Risk of Anti-tumor Drug Combination with hiPSC-CMs Based In Vitro Study

Figures

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  Fig. 1. Experimental design for evaluation of drug-induced cardiotoxicity in hiPSC-CMs. (A) Influences of different exposure extents (0, 1.25, 2.5, 5, 10, and 20 μM) and durations (6, 12, 24, 48, and 72 h) of doxorubicin on cardiomyocyte contractility. (B) Doxorubicin-trastuzumab interaction on cardiomyocyte contractility. Doxorubicin (5 μM) and trastuzumab (1 μM or 10 μM) were given alone, sequentially, or concurrently.

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  Fig. 2. The diagram of potential TD models for drug induced systolic dysfunction. Lines ending in closed circles indicate an effect is being exerted. Open and solid boxes differentiate between stimulatory and inhibitory effects. Dashed lines indicate that arrow-pointed physiological parameters can be calculated by the amount at the other end of lines.

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  Fig. 3. Overall structure of the in vitro-in vivo translational platform. The platform has four components. In the pharmacokinetic (PK) component, PBPK models convert the doses of antineoplastic agents to their free concentrations in the cytosol. In the mechanism-based toxicodynamic (TD) component, antineoplastic agent interaction and drug-cardiomyocyte interaction jointly determine the variations in survival fraction and average contractile force. The quantitative system pharmacology (QSP) component describes systemic responses to cardiomyocyte injury. Virtual patient trials were conducted to simulate and calculate systolic dysfunction incidence.

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  Fig. 4. Experimental design for virtual trials. TRZ: single-agent trastuzumab group; DOX → TRZ: sequential administration of doxorubicin and trastuzumab; DOX + TRZ: concurrent administration of doxorubicin and trastuzumab.

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  Fig. 5. Model predictions (red line) and experimental observations (blue dot) for contractile force in hiPSC-CMs in response to doxorubicin. Red lines indicate model predictions and blue dots indicate experimental observations.

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  Fig. 6. Model predictions and experimental observations of contractile force, survival fraction, and ATP levels in hiPSC-CMs. Red lines indicate model predictions and blue dots indicate experimental observations. Doxorubicin (5 μM) and trastuzumab (1 μM or 10 μM) were given alone, sequentially, or concurrently.

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  Fig. 7. Observed and model predicted incidences of doxorubicin and trastuzumab induced systolic dysfunction. (A) Observed and model predicted incidences of doxorubicin-induced systolic dysfunction. The light green shadow represents prediction interval of the incidence. Lines in different colors represent incidence rates reported by different clinical trials [43–45]. Solid and dashed lines represent incidence rates for cardiovascular normal and diseased patients. (B) Observed and model predicted incidences of trastuzumab-induced systolic dysfunction [2–5, 49, 53–57]. The violin plots represent the distribution of incidence calculated in all virtual patients. Box plots represent simulated incidence of systolic dysfunction in patients in different cardiovascular conditions. Bubbles in different colors represent observed incidences reported by various clinical trials. TRZ: single-agent trastuzumab treatment; DOX → TRZ: sequential treatment of doxorubicin and trastuzumab; DOX + TRZ: concurrent treatment of doxorubicin and trastuzumab.