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

## TL;DR

This paper introduces a computational platform that predicts heart damage risks from cancer drug combinations using lab-grown heart cells.

## Contribution

A novel in vitro-in vivo translational platform was developed to predict systolic dysfunction from antineoplastic drugs using hiPSC-CMs.

## Key findings

- The platform successfully predicted systolic dysfunction trends for doxorubicin across cumulative doses.
- Trastuzumab-induced systolic dysfunction incidence predictions aligned with clinical observations.
- The model captured increased risk in trastuzumab-doxorubicin combination treatments.

## Abstract

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.

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.

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).

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.

The online version contains supplementary material available at 10.1007/s11095-023-03644-4.