Mitigating Trastuzumab-Doxorubicin Cardiotoxicity With Multiscale Quantitative Systems Toxicology and PBPK-Toxicodynamic Predictive Modeling Framework.

Abstract

Doxorubicin (DOX) and trastuzumab (TmAb) are widely used to treat HER2-positive breast cancer (BC), as monotherapies and in combination (DOX + TmAb). While highly effective, their combined use significantly increases the risk of irreversible cardiotoxicity, posing a major clinical concern. B-type natriuretic peptide (BNP) and NT-proBNP are serum biomarkers of early cardiotoxicity. Understanding the dynamic relationship between these biomarkers and intracellular apoptosis pathways is key to predicting and mitigating treatment-induced cardiotoxicity. This study aims to extend a previously developed multiscale modeling framework of DOX-induced cardiotoxicity to include DOX + TmAb combinatorial effects and to predict clinical outcomes. Human cardiomyocytes were exposed to different concentrations of DOX, TmAb, DOX + TmAb, or control for 96 h. Time-course data for caspase-9 and -3 expression, cell viability, and BNP were collected and used to develop mathematical models for intracellular apoptosis-signaling protein dynamics, cardiomyocyte viability, and cardiomyocyte injury biomarkers. The cellular model was scaled up to humans with a previously published TmAb human PBPK model using NT-proBNP data and evaluated with left ventricular ejection fraction measurements. The quantitative systems toxicology (QST) model successfully captured in vitro dynamic data across treatment groups. Caspase-3 drove the cardiomyocyte-death model. Multiplicative and additive relationships characterized drug interactions to reflect the enhanced cardiotoxicity seen with DOX + TmAb. The predicted clinical BNP changes were consistent with LVEF dynamics from BC patients treated with TmAb. The QST-PBPK model bridges in vitro experimental findings with clinical cardiotoxicity outcomes. It provides a predictive tool for cardiotoxicity, aiding potentially in dose optimization and clinical monitoring for HER2-positive BC patients.