Population pharmacodynamic analysis of erythropoiesis in preterm infants for determining the anemia treatment potential of erythropoietin

Abstract

Saleh MI, Nalbant D, Widness JA, Veng-Pedersen P. Population pharmacodynamic analysis of erythropoiesis in preterm infants for determining the anemia treatment potential of erythropoietin. Am J Physiol Regul Integr Comp Physiol 304: R772-R781, 2013. First published March 13, 2013 doi:10.1152/ajpregu.00173.2012.-A population pharmacokinetics/pharmacodynamic (PK/PD) model was developed to describe changes in erythropoiesis as a function of plasma erythropoietin (EPO) concentration over the first 30 days of life in preterm infants who developed severe anemia requiring red blood cell (RBC) transfusion. Several covariates were tested as possible factors influencing the responsiveness to EPO. Discarded blood samples in 27 ventilated preterm infants born at 24 -29 wk of gestation were used to construct plasma EPO, hemoglobin (Hb), and RBC concentration-time profiles. The amount of Hb removed for laboratory testing and that transfused throughout the study period were recorded. A population PK/PD model accounting for the dynamic Hb changes experienced by these infants was simultaneously fitted to plasma EPO, Hb, and RBC concentrations. A covariate analysis suggested that the erythropoietic efficacy of EPO is increased for preterm infants at later gestational ages. The PD analysis showed a sevenfold difference in maximum Hb production rate dependent on gestational age and indicated that preterm infants, when stimulated by EPO, have the capacity to produce additional Hb that may result in a decrease in RBC transfusions. The present model has utility in clinical trial simulations investigating the treatment potential of erythropoietic stimulating agents in the treatment of anemia of prematurity. erythropoiesis; preterm infants; pharmacodynamics; gestational age ANEMIA IS A FREQUENT COMPLICATION in very low birth weight (VLBW) premature infants (birth weight Ͻ1,500 g) that is usually referred to as anemia of prematurity (14). There are two main causes of anemia of prematurity: insufficient erythropoietin (EPO) production and heavy blood loss resulting from frequent laboratory blood sampling (53). Previous studies have shown that during the first 4 wk of life in preterm infants with a gestational age Ͻ28 wk or birth weights Ͻ1 kg, approximately twice the volume of red blood cells (RBCs) transfused relative to the volume removed for laboratory blood testing (50). Thus the effect of blood sampling is substantial and must be considered in the management of anemia and in the assessment of erythropoiesis in preterm infants. Anemia of prematurity is also exacerbated by other factors such as shortened RBC life span and the rapid expansion of blood volume with growth (32).For many years, RBC transfusion was the only effective treatment for severe anemia of prematurity. In 1987, the first clinical trial of EPO demonstrated that EPO treatment was demonstrated to reduce the need for RBC transfusions in adults with end-stage renal disease (18). Subsequently, there has been a series of reports demonstrating variable results regarding th...

Hematological Differences in Newborn and Aging: A Review Study

“…Factor contributing to decline in hematological parameters in the newborn was due to decrease in blood erythropoietin concentration soon after birth, reducing the erythropoietic rate. Also, transient hemolysis is high during the first days or week after birth as during the remainder of healthy life, this transient hemolysis is a general physiologic occurrence during the first week after birth similar to neocytolysis a rapid decline in hemoglobin, because of hemolysis, seen in mountaineers after they descend to sea level following many weeks at high altitude [8][9][10][11][12]. Significant hematologic differences are seen between term and preterm infants and among newborns, infants, young children and older children.…”

A Method to Evaluate Fetal Erythropoiesis from Postnatal Survival of Fetal RBCs

“…13 must be modified to accurately account for the perturbations in the Hb level caused by the phlebotomies. We accounted for the loss of labeled RBCs from circulation as previously described (18)(19)(20). Details of the phlebotomy correction are described in the Appendix.…”

“…The volume of packed RBCs administered (85% Hct) and the time of RBC transfusions were recorded for use in the analysis. The MCH parameter was set equal to 37.5 pg/cell based on previous estimates (18,19).…”

A Mass Balance-Based Semiparametric Approach to Evaluate Neonatal Erythropoiesis

“…Previous studies of neonatal erythropoiesis assumed specific structural pharmacodynamic (PD) models to describe the regulation of postnatal Hb production rate over time (11,12). In these models, the postnatal Hb production was assumed to be stimulated by Epo through a stimulation function.…”

“…In these models, the postnatal Hb production was assumed to be stimulated by Epo through a stimulation function. The stimulation function was related to plasma Epo concentrations by an E max model (11,12). While useful, this approach is highly dependent on defining the correct relationship between the plasma Epo levels and the Hb stimulation rate.…”