Mitigating Trastuzumab-Doxorubicin Cardiotoxicity With Multiscale Quantitative Systems Toxicology and...

Area of Science:

• Pharmacology and Toxicology
• Cardiovascular Research
• Computational Biology

Background:

• Doxorubicin (DOX) and trastuzumab (TmAb) are standard treatments for HER2-positive breast cancer (BC).
• Combined DOX + TmAb therapy increases cardiotoxicity risk, a significant clinical challenge.
• Biomarkers like B-type natriuretic peptide (BNP) and NT-proBNP indicate early cardiotoxicity.

Purpose of the Study:

• To extend a multiscale model of DOX-induced cardiotoxicity to incorporate DOX + TmAb combinatorial effects.
• To predict clinical cardiotoxicity outcomes using a quantitative systems toxicology (QST) approach.
• To integrate in vitro data with clinical measurements for a comprehensive predictive model.

Main Methods:

• Developed mathematical models for cardiomyocyte apoptosis pathways, viability, and injury biomarkers (BNP).
• Exposed human cardiomyocytes to DOX, TmAb, or DOX + TmAb, collecting time-course data.
• Scaled the cellular model to human physiology using a TmAb physiologically based pharmacokinetic (PBPK) model and NT-proBNP data.

Main Results:

• The QST model accurately reproduced in vitro dynamic data for all treatment groups.
• Caspase-3 was identified as the primary driver of cardiomyocyte death.
• Drug interactions were characterized as multiplicative and additive, explaining enhanced cardiotoxicity.
• Predicted clinical BNP changes correlated with left ventricular ejection fraction (LVEF) dynamics in BC patients.

Conclusions:

• The developed QST-PBPK model effectively links in vitro findings to clinical cardiotoxicity.
• This model serves as a predictive tool for assessing and managing treatment-induced cardiotoxicity.
• Potential applications include optimizing drug dosage and enhancing clinical monitoring for HER2-positive BC patients.