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

Abstract

Objective: Antineoplastic agent-induced systolic dysfunction is a major reason for interruption of anticancer treatment. Although targeted anticancer agents infrequently cause systolic dysfunction, their combinations with chemotherapies remarkably increase the incidence. Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) provide a potent in vitro model to assess cardiovascular safety. However, quantitatively predicting the reduction of ejection fraction based on hiPSC-CMs is challenging due to the absence of the body's regulatory response to cardiomyocyte injury.

Methods: Here, we developed and validated an in vitro-in vivo translational platform to assess the reduction of ejection fraction induced by antineoplastic drugs based on hiPSC-CMs. The translational platform integrates drug exposure, drug-cardiomyocyte interaction, and systemic response. The drug-cardiomyocyte interaction was implemented as a mechanism-based toxicodynamic (TD) model, which was then integrated into a quantitative system pharmacology-physiological-based pharmacokinetics (QSP-PBPK) model to form a complete translational platform. The platform was validated by comparing the model-predicted and clinically observed incidence of doxorubicin and trastuzumab-induced systolic dysfunction.

Results: A total of 33,418 virtual patients were incorporated to receive doxorubicin and trastuzumab alone or in combination. For doxorubicin, the QSP-PBPK-TD model successfully captured the overall trend of systolic dysfunction incidences against the cumulative doses. For trastuzumab, the predicted incidence interval was 0.31-2.7% for single-agent treatment and 0.15-10% for trastuzumab-doxorubicin sequential treatment, covering the observations in clinical reports (0.50-1.0% and 1.5-8.3%, respectively).

Conclusions: In conclusion, the in vitro-in vivo translational platform is capable of predicting systolic dysfunction incidence almost merely depend on hiPSC-CMs, which could facilitate optimizing the treatment protocol of antineoplastic agents.

Keywords: cancer therapy; cardiac toxicity; in vitro to in vivo translation; pluripotent stem cells; quantitative systems pharmacology.

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.

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.

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.

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.

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.

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.

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 [–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 [–, , –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.