Journal: CPT: Pharmacometrics & Systems Pharmacology
Article Title: Mitigating Trastuzumab‐Doxorubicin Cardiotoxicity With Multiscale Quantitative Systems Toxicology and PBPK‐Toxicodynamic Predictive Modeling Framework
doi: 10.1002/psp4.70087
Figure Lengend Snippet: Model Structure of the Combinatorial Effects of DOX and TmAb on AC16 Cells. The model is divided into three primary components: (1) Protein Dynamics Model for Apoptosis: This segment includes the Caspase‐9 (Cas9S, Cas9 1–2 ) and Caspase‐3 (Cas 1–3 ) compartments, with Cas9 2 and Cas3 3 (indicated by green circles) representing the measured apoptotic protein responses to the individual and combined effects of DOX and TmAb. (2) Cardiomyocyte Injury Biomarker Model: This model features compartments for B‐type natriuretic peptide (BNP 1–3 ), with BNP 3 (marked by an orange circle) as the key biomarker indicating cardiotoxicity in response to both single‐agent and combinatorial treatments of DOX and TmAb. (3) Cardiomyocyte‐Death Model: This model incorporates two transit compartments (Tr 1–2 ) associated with the Cas3 3 response, which affects the viability compartment (R). Compartment R reflects the relative viability of AC16 cells under DOX and TmAb treatments, alone and in combination. The parameters k cas9 , k cas3 , k bnp , k Tr , and k g , represent first‐order rate constants for the respective responses within their corresponding transit compartments. The parameter kd1 captures the cell death dynamics related to Cas3 3 influencing the viability compartment R , while kd2 defines the inhibition slope of cell growth due to DOX. Detailed descriptions of all parameters are provided in Table .
Article Snippet: Essential assay kits included BCA protein assay, protease inhibitor cocktail, human cardiac troponin I ELISA kit, and human B‐type natriuretic peptide (BNP) ELISA kit from Thermo Fisher Scientific (Waltham, MA).
Techniques: Biomarker Discovery, Inhibition