An integrated pharmacodynamic analysis of erythropoietin, reticulocyte, and hemoglobin responses in acute anemia.
OBJECTIVE
To determine by pharmacodynamic (PD) analysis physiologically relevant parameters of the cellular kinetics of erythropoiesis in acute anemia.


METHODS
The PD relationships among erythropoietin (EPO), reticulocyte, and RBC (Hb) responses were investigated in young adult sheep in acute anemia induced twice by two controlled phlebotomies separated by a 4-week recovery period.


RESULTS
The phlebotomies resulted in rapid increases in plasma EPO, with maximal levels occurring at 3 to 8 days, followed by a reticulocyte response with a delay of 0.5 to 1.5 days. The Hb returned to prephlebotomy base line at the end of the 4-week recovery period. The EPO, reticulocyte count, and Hb responses were well described by a PK/PD model (r = 0.975) with the following cellular kinetics parameters: the lag time between EPO activation of erythroid progenitor cells and reticulocyte formation; the reticulocyte-to-RBC maturation time; the reticulocyte and Hb formation efficacy coefficients, quantifying EPO's efficacy in stimulating the formation of reticulocytes and Hb, respectively; the C50 PK/PD transduction parameter defined as the EPO level resulting in half the maximum rate of erythropoiesis.


CONCLUSIONS
Physiologically relevant cellular kinetics parameters can be obtained by an endogenous PK/PD analysis of phlebotomy data and are useful for elucidating the pathophysiologic etiology of various anemias.
Veng-Pedersen
P
P
University of Iowa, College of Pharmacy, Division of Pharmaceutics, Iowa City, Iowa, 52242, USA. veng@uiowa.edu
Chapel
S
S
Schmidt
R L
RL
Al-Huniti
N H
NH
Cook
R T
RT
Widness
J A
JA
D000208:Acute Disease; D000740:Anemia / Q000097:blood*; D000818:Animals; D004921:Erythropoietin / Q000097:blood*; D006454:Hemoglobins / Q000378:metabolism*; D018962:Phlebotomy / Q000009:adverse effects; D012156:Reticulocytes / Q000378:metabolism*; D012756:Sheep
D006454:Hemoglobins; D004921:Erythropoietin