Erythropoietin pharmacokinetic/pharmacodynamic analysis suggests higher doses in treating neonatal anemia

Erythropoietin (EPO) is the principal hormone regulating red blood cell (RBC) production and is primarily produced in the kidney.1 EPO receptors (EPOR) have been detected in the brain, retina, heart, skeletal muscles, kidneys and endothelial cells, 2–4 suggesting other functions of EPO in addition to its erythropoietic properties. Recombinant human EPO (r-HuEPO) is most widely used as an effective treatment modality for anemic patients with insufficient EPO production, for example in end-stage renal disease, and for the treatment of anemia associated with cancer chemotherapy. Anemia of prematurity, commonly observed during the first few weeks after birth in very low-birthweight infants, is generally treated with RBC transfusions. 5,6 Approximately 70–80% of the transfusions are given during the first 4 weeks7 when the postnatal hemoglobin (Hb) drop begins to occur.8–10. The anemia is exaggerated by iatrogenic phlebotomy losses, decreased RBC survival and reduced EPO levels.10–14 The markedly low EPO concentrations for the degree of anemia seen in premature infants have been assumed to reflect decreased EPO production. 15,16 There is, however, experimental evidence of expanded plasma volume and increased EPO clearance compared to adults, which could be a plausible explanation for the reduced EPO concentrations.17–20 In addition to these decreased levels, bone marrow erythroid hypoplasia21 and also the sensitivity of fetal and neonatal progenitors to EPO in vitro22,23 being comparable to those of adults provide a rationale for the use of r-HuEPO as a potential therapy for anemic neonates. But controlled trials of r-HuEPO have resulted in contradictory views regarding its use. While some studies have shown that it is beneficial in reducing RBC transfusions,11,24–28 others have seen little to no significant difference between control and r-HuEPO treatment groups. 29–33 Recombinant human EPO was primarily developed for treatment of anemia in adults. Accordingly, in its drug development, the recommended dosing was determined only for this patient population. As is often the case, optimal dosing for neonates was not established in the drug development stage. Investigations of the treatment of neonatal anemia with r-HuEPO in clinical trials have largely been based on adult per kg dosing, which proved to be less efficacious in infants. The progressive developmental decrease in the clearance of r-HuEPO from fetus to adult indicates that doses higher than those used for adults are required for the effective treatment of neonatal anemia. Moreover, the dynamic changes in the erythroid receptor pool in response to anemia and prior exposure to EPO emphasize the need for proper optimization of the timing and dosing of r-HuEPO, which can be obtained through controlled pharmacokinetic/pharmacodynamic (PK/PD) experiments. The main purpose of this study was to make predictions about the efficacy of EPO at higher doses. This is done by investigating the PK/PD relationship between EPO and its pharmacologic effect of activation and differentiation of the erythroid precursors to reticulocytes using the sheep/lamb animal model. The analysis provides insight into the maximum achievable activation by EPO, thereby providing information on the peak EPO concentrations and maximal EPO dosing that can be attained without any significant saturation of the EPOR pool that would result in diminished efficacy. The endogenous EPO levels observed in the preclinical phlebotomy experiments were generally below the saturable limits and comparable to the levels seen in clinical dosing situations, thus lending support to the administration of higher r-HuEPO doses to treat anemia of prematurity.