Simultaneous pharmacokinetics/pharmacodynamics modeling of recombinant human erythropoietin upon multiple intravenous dosing in rats

Abstract

A pharmacokinetics (PK)/pharmacodynamics (PD) model was developed to describe the tolerance and rebound for reticulocyte (RET) and red blood cell (RBC) counts and the hemoglobin (Hb) concentrations in blood after repeated intravenous administrations of 1350 IU/kg of recombinant human erythropoietin (rHuEPO) in rats thrice weekly for 6 weeks. Drug concentrations were described by using a quasi-equilibrium model. The PD model consisted of a lifespan-based indirect response model (LIDR) with progenitor cells [burst colony-forming unit erythroblasts and colony-forming unit erythroblasts (CFUs)], normoblasts (NOR), RETs, and RBCs. Drug-receptor complex stimulatory effects on progenitor cells differentiation and RBC lifespan were expressed by using the E(max) model (S(max-epo) and SC(50-epo), E(max) and EC(50)). The Hb profile was indirectly modeled through a LIDR model for mean corpuscular hemoglobin (with a lifespan T(mch)) including a linear (S(max-mch)) drug stimulatory effect. The negative feedback from RBCs accounted for the time-dependent rHuEPO clearance decline. A simultaneous PK/PD fitting was performed by using MATLAB-based software. PK parameters such as equilibrium dissociation, erythropoietin receptor degradation, production, and internalization rate constants were 0.18 nM (fixed), 0.08 h(-1), 0.03 nM/h, and 2.51 h(-1), respectively. The elimination rate constant and central volume of distribution were 0.57 h(-1) and 40.63 ml/kg, respectively. CFU and NOR, RET, and RBC lifespans were 37.26 h, 17.25 h, and 30.15 days, respectively. S(max-epo) and SC(50-epo) were 7.3 and 0.47 10(-2) nM, respectively. E(max) was fixed to 1. EC(50) and SC(50-epo) were equal. S(max-mch) and T(mch) were 168.1 nM(-1) and 35.15 days, respectively. The proposed PK/PD model effectively described rHuEPO nonstationary PK and allowed physiological estimates of cell lifespans.

Fig. 1.

Schematic diagram of the simultaneous PK/PD model for rHuEPO on blood reticulocytes, red blood cells, and mean corpuscular hemoglobin. Symbols are defined under Appendix.

Fig. 2.

Time course profiles of rHuEPO serum concentrations after multiple intravenous injections of 1350 IU/kg thrice weekly for 6 weeks. The observed data are represented by ○, and the lines represent the model predictions using eq. 4. The arrows represent intravenous dosing events.

Fig. 3.

Time course profiles of absolute blood reticulocyte counts (top left), red blood cells (top right), mean corpuscular hemoglobin (bottom left), and hemoglobin (bottom right). The observed data are represented by ○. The solid lines represent the model predictions using eqs. 22 (top left), 23 (top right), 24 (bottom left), and 28 (bottom right). The arrows represent intravenous dosing events.

Fig. 4.

Top, mean serum transferrin concentration-time profile. Bottom, mean serum ferritin concentration-time profile. Means (n = 12) ± S.D. of treated animals (●) and means (n = 3) ± S.D. for the control animals (○) are shown.

Fig. 5.

Changes in baselines values of absolute blood reticulocyte counts (top left), red blood cells (top right), mean corpuscular hemoglobin (bottom left), and hemoglobin (bottom right). The observed data are represented by ○, and the lines represent the model predictions using eq. 29 (top left), eq. 30 (top right), MCH baseline (bottom left), and eq. 28 (bottom right), respectively.

Fig. 6.

Time course profiles of model-predicted hematological responses after single intravenous doses of 1350 IU/kg using the final parameter estimates and E_max fixed to 1. Top left, simulated RETs. Top right, simulated RBCs. Bottom left, simulated MCH. Bottom right, simulated Hb.

Fig. 7.

Time course profiles of model-predicted RBC(t) after a single intravenous dose of 1350 IU/kg using the final parameter estimates and different E_max values.

Fig. 8.

Time course profiles of model-predicted R_tot(t), RC(t), and R(t) concentrations. Top, total EPOR pool concentrations time course profile, R_tot(t). Middle, rHuEPO–EPOR complexes concentration time course profile, RC(t). Bottom, free EPOR concentration time course profile, R(t).

Fig. 9.

Time course profiles of model-predicted rHuEPO clearance pathways. Top, model-predicted linear clearance time course profile, CL_lin(t). Middle, model-predicted EPOR mediated clearance time course, CL_rec(t). Bottom, model-predicted total rHuEPO clearance time course, CL_Total(t).

Fig. 10.

Time course profile of model-predicted mean RBC lifespan, ML_RBC(t).