RT Journal Article
SR Electronic
T1 Simultaneous Pharmacokinetics/Pharmacodynamics Modeling of Recombinant Human Erythropoietin upon Multiple Intravenous Dosing in Rats
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 897
OP 910
DO 10.1124/jpet.110.167304
VO 334
IS 3
A1 Sihem Ait-Oudhia
A1 Jean-Michel Scherrmann
A1 Wojciech Krzyzanski
YR 2010
UL http://jpet.aspetjournals.org/content/334/3/897.abstract
AB 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 Emax model (Smax-epo and SC50-epo, Emax and EC50). The Hb profile was indirectly modeled through a LIDR model for mean corpuscular hemoglobin (with a lifespan Tmch) including a linear (Smax-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. Smax-epo and SC50-epo were 7.3 and 0.47 10−2 nM, respectively. Emax was fixed to 1. EC50 and SC50-epo were equal. Smax-mch and Tmch 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.