Erythropoietin pharmacokinetic/pharmacodynamic analysis suggests higher doses in treating neonatal anemia.
BACKGROUND
The establishment of effective treatment of neonatal anemia using recombinant human erythropoietin (r-HuEPO) requires a thorough understanding of the physiology and mechanism of EPO's pharmacologic effect. The purpose of the present preclinical study in sheep was to elucidate the stimulatory effect of EPO on erythroid progenitors and their differentiation into reticulocytes useful in predicting optimal r-HuEPO dosing.


METHODS
Five young adult sheep each underwent two phlebotomies spaced 4-6 weeks apart in which their hemoglobin levels were reduced from 12 g/dL to 3-4 g/dL. Endogenous EPO levels and reticulocyte counts produced in response to anemia were sampled throughout the study and analyzed using a pharmacokinetic/pharmacodynamic (PK/PD) model.


RESULTS
The phlebotomy-induced drop in hemoglobin resulted in a increase in EPO levels, which reached a maximum of 764 +/- 55 mU/mL (mean +/- %CV) in 0.5-2.6 days. The reticulocyte counts increased from baseline values of 76.9 x 10(3) +/- 67/microL to 619 x 10(3) +/- 30/microL in 8 days. The PK/PD analysis indicated an increased maturation time for the reticulocytes (4.88 +/- 35 days) and demonstrated that the E(max) model for EPO's activation of the progenitors did not show significant effect saturation at the endogenous EPO levels reached.


CONCLUSIONS
In extrapolating from the animal pilot experiment, the present study provides a case for the use of higher r-HuEPO doses in human studies to determine if higher doses are more effective in treatment of neonatal anemia to reduce, and in some less severe cases, eliminate, the need for blood transfusions.
Neelakantan
Srividya
S
Division of Pharmaceutics, College of Pharmacy, University of Iowa, Iowa City, Iowa 52242, USA.
Widness
John A
JA
Schmidt
Robert L
RL
Veng-Pedersen
Peter
P
D000751:Anemia, Neonatal / Q000188:drug therapy*; D000818:Animals; D004921:Erythropoietin / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D006801:Humans; D007231:Infant, Newborn; D010865:Pilot Projects; D011994:Recombinant Proteins; D012756:Sheep
D011994:Recombinant Proteins; D004921:Erythropoietin