Figure 8.

Mechanism-based PK-PD model of ESAs. The upper panel of the flow schematic is based on the TMDD model to describe the PK process. D and A_D represent the duration of the zero-order input and absorption compartment for the SC route, respectively. F is the bioavailability, and k_a is the first-order absorption rate constant. C _A, C _B, and RC represent the concentration of free ESAs, endogenous EPO (eEPO), and the EPO-receptor complex, respectively. A_TA and A_TB are tissue compartments, k _tpA, k _tpB, k _ptA, and k _ptB are tissue distribution rate constants; k _onA, k _onB, k _offA, and k _offB represents second-order rate constants for forming RC and first-order dissociation rate constants of ESAs and eEPO; R_tot represents total receptor concentration; CL_A and CL_B are the first-order elimination rate constants; k _int is the first-order internalization and degradation rate constant; k _EPO represents the synthesis rate of eEPO. The PD model contains delay parameters, indicating the life span of various erythropoietic cells. P ₁, P ₂, and P ₃ represent three different maturation-level erythroid precursor cell compartments; RET is reticulocytes, and RBCM is mature red blood cell; HGB represents hemoglobin. K _IN0 represents production process for P₁ cells, S _max represents the maximal effect of RC on the proliferation of precursor cells, and SRC₅₀ is the concentration of drug-receptor complex to induce half of S _max; T _P, T _R, T _B, mean residence time for precursor cell, reticulocytes, and mature red blood cell. PD effect of the expansion of precursor cell on R_tot mediates the PK process in return, and ξ is the factor of proportionality.