Figure 7.

The PK-PD model of the free doxorubicin and liposomal doxorubicin. Free doxorubicin and liposomal doxorubicin are represented by white and grey circles, respectively; the disposition of free doxorubicin and liposomal doxorubicin was described by a two-compartment and a one-compartment model, respectively. The intra-tumor disposition is described by a physiological model linked with tumor blood flow rate (Q). Tumor tissue was divided into three compartments: capillary (CAP), interstitial (INT), and tumor cell. The former two are considered in the extracellular compartment (ESC). k_RES represents reticuloendothelial system (RES) mediated elimination rate constant of liposomal doxorubicin; liposomal doxorubicin was unidirectionally transported from CAP into INT (k _tu); k _rel represents the first-order release rate constant of free doxorubicin from liposomes in blood, CAP and INT; distribution of free doxorubicin to tumor cells was described using k_te and k _et; k ₂₁, k ₁₂, and k ₁₀ represent the micro-pharmacokinetic constants for free doxorubicin. For the pharmacodynamic model, a cell-kill kinetic model was linked with the PK model. The mass balance equation describes the change rate of cell number, where C_s represents cell number, f _b ∙C _ecs represents the unbound drug concentration in ESC, k_s is the cell proliferation rate constant, and k is the drug-induced irreversible cell-death rate constant.