RT Journal Article
SR Electronic
T1 Pharmacokinetic and Pharmacodynamic Modeling of Recombinant Human Erythropoietin after Intravenous and Subcutaneous Administration in Rats
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 1297
OP 1306
DO 10.1124/jpet.106.111377
VO 319
IS 3
A1 Sukyung Woo
A1 Wojciech Krzyzanski
A1 William J. Jusko
YR 2006
UL http://jpet.aspetjournals.org/content/319/3/1297.abstract
AB The pharmacokinetics (PK) and pharmacodynamics (PD) of recombinant human erythropoietin (rHuEPO) were studied in rats after single i.v. and s.c. administration at three dose levels (450, 1350, and 4050 IU/kg). The plasma concentrations of rHuEPO and its erythropoietic effects including reticulocyte (RET), red blood cell (RBC), and hemoglobin (Hb) levels were determined. A two-compartment model with dual input rate and nonlinear disposition was used to characterize the PK of rHuEPO. The catenary indirect response model with several compartments reflecting the bone marrow and circulating erythropoietic cells was applied. The s.c. doses exhibited slow absorption (Tmax = 12 h) and incomplete bioavailability (F = 0.59). In placebo groups, RBC and Hb values gradually increased over time with growth of the rats, and the changes in the baselines monitored from 8 to 32 weeks of age were described by a nonlinear growth function. All doses resulted in dose-dependent increases in RET counts followed by an immediate decline below the baseline at around 6 days and returned to the predose level in 21–24 days after dosing. A subsequent steady increase of RBC and Hb levels followed and reached peaks at 6 days. A tolerance phenomenon observed at all dose levels was modeled by a negative feedback inhibition with the relative change in Hb level. The PK/PD model well described the erythropoietic effects of rHuEPO as well as tolerance, thereby yielding important PD parameters (Smax = 1.87 and SC50 = 65.37 mIU/ml) and mean lifespans of major erythropoietic cell populations in rats.