PT-028 - MITIGATING CARDIOTOXICITY OF TRASTUZUMAB AND DOXORUBICIN COMBINATION THERAPY WITH AN INTEGRATED TRANSLATIONAL AND QUANTITATIVE SYSTEMS TOXICOLOGY AND PBPK/PD MODELING APPROACH

S. Yu¹, H. Mody², T. Vaidya², L. Kagan¹, S. Ait-Oudhia³; ¹Department of Pharmaceutics and Center of Excellence for Pharmaceutical Translational Research and Education, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ, USA, ²Center for Pharmacometrics and Systems Pharmacology, Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, FL, USA, ³Quantitative Pharmacology and Pharmacometrics (QP2), Merck & Co., Inc, Kenilworth, NJ, USA.

Background: Doxorubicin (DOX) and trastuzumab (TmAb) are widely used to treat HER2-positive breast cancer (BC), as monotherapies and in combination (DOX+TmAb). While both are effective, they can cause irreversible cardiotoxicity, especially when combined. A previously developed multiscale quantitative systems toxicodynamic (QST) model characterized DOX-induced cardiotoxicity. This study aims to extend this model to include DOX+TmAb cardiotoxic effects and to scale up to clinical data.

Methods: AC16 cells were exposed to different concentrations of DOX, TmAb, DOX+TmAb, or control for 96h. CCK-8 assay was used for cell viability measurement. Caspase-9 and -3 were quantified with MULTIPLEX kits. B-type natriuretic peptide (BNP) was measured via ELISA. Data were normalized to baseline and used to develop models for cellular viability, protein dynamics, and cardiomyocyte injury biomarkers. The cellular model was scaled up to humans and evaluated with a previously published TmAb human PBPK model.

Results: The QST model accurately represented dynamic changes in caspase-9, -3, cellular viability, and BNP. Caspase-3 drove the AC16 cardiomyocytes-death model. Multiplicative and additive relationships characterized DOX, TmAb, and DOX+TmAb effects on caspase-9, -3, and BNP. The estimated caspase-9 and -3 turnover rate constants were 0.083 and 0.87h⁻¹. The BNP turnover rate constant was 0.20h⁻¹ (fixed). The scaling factor for clinical TmAb-induced BNP release was 0.86.

Conclusion: The QST model effectively captured all observed data. The scaled clinical BNP model, qualified with clinical NT-ProBNP and left ventricular ejection fraction data, provides a predictive tool for cardiotoxicity, aiding potentially in dose optimization and clinical monitoring for HER2-positive BC patients.