Efficacy of different dosing regimens for recombinant human erythropoietin in a simulated perisurgical setting: the importance of iron availability in optimizing response.
OBJECTIVE
The goal of this study was to develop a short-term, practical, yet effective regimen for the perioperative use of recombinant human erythropoietin (r-HuEPO) as an alternative to autologous blood donation and/or homologous transfusion. In addition, changes in iron kinetics during accelerated erythropoiesis were examined.


METHODS
A randomized trial was performed on 24 healthy, iron-replete men. Subjects were given r-HuEPO in one of three dosage schedules, receiving a total dose of 1200 U/kg r-HuEPO subcutaneously: Group I--300 U/kg on Days 1, 4, 7, and 10; Group II--400 U/kg on Days 1, 5, and 9; Group III--600 U/kg on Days 1 and 10. All subjects received 300 mg of elemental iron orally each day for 10 days beginning on Day 1. Complete blood counts (CBC), absolute reticulocyte counts, serum ferritin, serum iron, serum total iron-binding capacity (TIBC), and serum transferrin receptor protein concentrations were measured periodically during the 24-day study period.


RESULTS
All groups showed a statistically significant increase in hematocrit, hemoglobin, and absolute reticulocyte count. There was no significant difference in response among the three groups with respect to hemoglobin and hematocrit. The mean maximum increases in hematocrit were 5.4 +/- 1.7, 6.0 +/- 2.1, and 7.2 +/- 2.6 in groups I, II, and III, respectively. The increase in hematocrit positively correlated with log baseline ferritin (r = 0.682, p < 0.001). Administration of r-HuEPO was associated with a highly significant (p < or = 0.0005) 74% decrease in serum ferritin, as well as a marked decrease in percent saturation of TIBC from 39% +/- 14% to 14% +/- 4% (p < or = 0.0005). This was despite the fact that subjects lost less than 250 mL of blood as a result of venipunctures during the entire course of the study.


CONCLUSIONS
Each of these r-HuEPO dose schedules provides an effective, convenient regimen for perisurgical use. However, "normal" iron stores for basal erythropoiesis may not always be sufficient to supply optimal amounts of iron for the accelerated erythropoiesis associated with acute r-HuEPO administration, even with oral iron supplementation. Nonetheless, these findings provide support for further study of the use of r-HuEPO as an alternative to autologous blood donation in the perisurgical setting.
Rutherford
C J
CJ
Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts 02115.
Schneider
T J
TJ
Dempsey
H
H
Kirn
D H
DH
Brugnara
C
C
Goldberg
M A
MA
D001682:Biological Availability; D001803:Blood Transfusion; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004909:Erythrocyte Indices; D004920:Erythropoiesis / Q000502:physiology; D004921:Erythropoietin / Q000008:administration & dosage* / Q000627:therapeutic use; D005293:Ferritins / Q000097:blood; D006400:Hematocrit; D006801:Humans; D007501:Iron / Q000493:pharmacokinetics*; D008297:Male; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000627:therapeutic use; D017701:Reticulocyte Count; D013514:Surgical Procedures, Operative / Q000379:methods*
D011994:Recombinant Proteins; D004921:Erythropoietin; D005293:Ferritins; D007501:Iron