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

Figures

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  FIGURE 1. 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, Cas91–2) and Caspase‐3 (Cas1–3) compartments, with Cas92 and Cas33 (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 (BNP1–3), with BNP3 (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 (Tr1–2) associated with the Cas33 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…

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  FIGURE 2. Model fittings for cellular apoptotic signaling protein dynamics after DOX and TmAb treatment. Relative protein expression of caspase‐9 (left) and ‐3 (right) were shown. For each measurement, AC16 cells were exposed in 100 nM of DOX, 25 μΜ of TmAb, 50 nM of DOX with 12.5 μΜ of TmAb, and the control (no treatment) over 72 h. Blue dots represented the observation data and the purple curves represented model fittings.

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  FIGURE 3. Model fittings for AC16 cell viability after DOX and TmAb treatment. AC16 cells were exposed in DOX only (1.1, 10.5 and 25 nM), TmAb only (13.3, 23, and 28.4 μM), combination of DOX and TmAb (each DOX concentration + each TmAb concentration), and control (no treatment) over 96 h. Blue dots represented the observation data and the purple curves represented model predictions.

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  FIGURE 4. Model fittings for cellular cardiomyocyte injury biomarker BNP after DOX and TmAb treatment. AC16 cells were exposed in 25 nM of DOX, 23 μM of TmAb, combination of DOX and TmAb (25 nM + 23 μM), and control (no treatment) over 72 h. Blue dots represented the observation data and the purple curves represented model predictions.

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  FIGURE 5. Model fittings for human cardiomyocyte injury biomarker BNP after two cycles of TmAb treatment. Breast cancer patients were treated with dose of 8 mg/kg over 90 min IV infusion, then 6 mg/kg over 30 to 90 min IV infusion 3 weeks later [37]. Orange dots with error bars represented the mean ± sd of relative BNP levels converted from human NT‐Pro BNP observation data at each time point and the black curve represented model predictions.

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  FIGURE 6. Human cardiomyocyte injury biomarker model simulation result. Relative released BNP levels were simulated at pre‐dose, 3, 6, 9, 12, 15, and 18 months after dose. The TmAb treatment duration was 12 months. Treatment was initiated with 8 mg/kg over 90 min IV infusion at time 0, then with 6 mg/kg over 30 to 90 min IV infusion once every 3 weeks [37]. Blue bars represented the relative BNP levels model predictions and the orange blocks represented the relative BNP levels converted from LVEF observations from literature.