Figure 9.

The multiscale PK-PD model of brentuximab-vedotin. The PK model is an integration of a modified two-compartment model in tumor to simultaneously characterize the plasma and intracellular PK of ADC and the payload. After the IV administration of ADC, partial ADC dissociates and releases payloads. ADC and the free drug in the central compartment can be eliminated, distribute to the peripheral compartment, or distribute to the tumor compartment. In the tumor tissue, the free drug could enter the cell by passive diffusion and bind to the target or go back into the extracellular environment. ADC in the tumor environment interacts with the antigen on the tumor cell membrane, and is internalized into the tumor cell. Subsequently, ADC is degraded in lysosomes to release the free drug intracellularly. The intracellular concentration is considered as the concentration in the biophase compartment. X1_ADC, X2_ADC, X1_PL, and X2_PL, the amount of ADC or payload in the central or peripheral compartment; V1_ADC, V2_ADC, V1_PL, and V2_PL, volume of distribution of ADC or payload in the central or peripheral compartment; CL_ADC, plasma clearance of ADC; CLD_ADC, distribution clearance of ADC; ADC_Free and ADC_Bound, free and bound ADC concentration in tumor tissue; Ag: total antigen; PL_Free and PL_Bound, free and bound payload concentration in cancer cell; DAR, average drug antibody ratio; k _dis, dissociation rate of payload from antibody-drug conjugate; k_{i nt} ^Ag, internalization rate of antigen inside the cell; k _on ^ADC and k _off ^ADC, association and dissociation rate constants between antibody-drug conjugate and antigen; k _on ^PL and k _off ^PL, association and dissociation rate constants between drug and intracellular drug target; k_{i n} ^PL, drug nonspecific uptake rate in cancer cell; k _out ^PL, efflux rate of payload from the cancer cell; V1, V2, V3, and V4, tumor volume in the growth.