A pharmacodynamic analysis of erythropoietin-stimulated reticulocyte response in phlebotomized sheep

The pharmacodynamics (PD) of the reticulocyte response resulting from phlebotomy-induced erythropoietin (EPO) was investigated in adult sheep. The anemia caused by the controlled phlebotomy (Hb < 4 g/dl, t = 0) resulted in a rapid increase in EPO with peak concentrations from 200 to 1400 mU/ml at 0.5 to 3 days generating a delayed reticulocyte response with peak levels from 9.3 to 14.1% at 2.5 to 5.1 days. The PD EPO-reticulocyte relationship is well described by a simple kinetic model involving 3 relevant physiologic parameters: T(1) = lag-time (0.73 +/- 0.32 days, mean +/- S.D.), T(2) = reticulocyte maturation time (5.61 +/- 1.41 days), and k = EPO efficacy coefficient (0.052 +/- 0.048% g/dl mU/ml/day). Accordingly, 0.52% reticulocytes at 10 g/dl Hb level are generated per day at an EPO concentration of 100 mU/ml. The difference between the T(2) parameter in this study and the maturation time reported for humans may be due to interspecies differences or different technique and experimental conditions. The PD transduction appears largely linear in the observed EPO concentration range, indicating a full utilization of EPO without any significant PD saturation. Also, the EPO concentration versus time profiles resulting from the phlebotomy were similar to exogenous EPO profiles resulting from s.c. therapeutic dosing. This study supports the hypothesis that s.c. EPO dosing is more efficacious than i.v. dosing.