Precision Cardio-Oncology: Use of Mechanistic Pharmacokinetic and Pharmacodynamic Modeling to Predict Cardiotoxicities of Anti-Cancer Drugs

Figures

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  Figure 1. Illustrative structure of a dynamic hERG-binding model. The left part corresponds to the physiological component of the model, where C1 and C2 represent the closed states of the channel and O represents the open state, with the corresponding inactivated states indicated as IC1, IC2, and IO, respectively. The right part represents the pharmacodynamic component, which assumes three drug-bound states: open bound (O*), inactivated open bound (IO*), and closed bound (C*). The drug can be trapped in the C* state.

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  Figure 2. Schematic representation of the PK-PD model corresponding to the relationship between the left ventricular ejection fraction and trastuzumab exposure.

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  Figure 3. Illustrative structure of the hemodynamic system pharmacology model developed by Snelder et al. (23). HR, heart rate; TPR, total peripheral resistance; MAP, mean arterial pressure; and SV, stroke volume. FB- represents the negative feedback mechanism through MAP. The effects on HR, SV, and TPR are described using turnover models. Kin_HR, Kin_SV, and Kin_TPR represent the zero-order production rate constants and kout_HR, kout_SV, and kout_TPR represent the first-order elimination rate constants.

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  Figure 4. Schematic diagram of the developed multiscale PB-PK model for doxorubicin. (A) Whole-body PB-PK model comprising seven tissues and two blood compartments. The blood compartments are further divided into plasma and blood cell sub-compartments. (B) Tissue model; each tissue is divided into the vascular, interstitial, intracellular, and nucleus DNA-bound sub-compartments.

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  Figure 5. Key signal transduction pathways involved in dasatinib- and sorafenib-induced toxicity in cardiomyocytes. AKT, AKT8 virus oncogene cellular homolog; BAD, Bcl2-associated death promoter; BAX, Bcl2-associated X protein; Bcl-2, B-cell lymphoma 2 protein; Bcl-xl, B-cell lymphoma extra-large protein; Bcr-Abl, fusion protein encoded by the Philadelphia chromosome; Casp-3, caspase-3; Casp-9, caspase-9; c-KIT, stem cell growth factor receptor; Cyt, C cytochrome c; EGFR, epidermal growth factor receptor; ERK, extracellular signal regulated kinase; JNK, Jun N-terminal kinase; MAPK, mitogen activated protein kinase; MEK, MAPK/ERK kinase; mTOR, mammalian target of rapamycin; PDGFR, platelet derived growth factor receptor; PI3K, phosphoinositide 3 kinase; RAF, rapidly accelerated fibrosarcoma kinase protein; RAS, prototypical member of the Ras superfamily of proteins (belonging to the small GTPase group of proteins); Src Rous, sarcoma oncogene cellular homolog tyrosine kinase protein; TNFR1, tumor necrosis factor receptor 1; VEGFR, vascular endothelial growth factor receptor.