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

Abstract

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.

Keywords: erythropoiesis; gestational age; pharmacodynamics; preterm infants.

Fig. 1.

Pharmacodynamic model for the effect of erythropoietin (EPO) on Hb production and disposition. See Glossary for terms.

Fig. 2.

Pharmacodynamic Hb mass balance model fit to 3 representative infant study subjects (A–C). The first 2 rows represent plots of observed, population-predicted, and individual-predicted values of plasma concentrations of Hb and RBC vs. time profiles, respectively. The last row represents the observed values of EPO concentration (left y-axis) and body weight (right y-axis).

Fig. 3.

Amount of Hb transfused over the first month of life vs. gestational age for the 27 study subjects.

Fig. 4.

Observed Hb concentrations and RBC counts (top and bottom, respectively) vs. population-predicted and individual-predicted concentrations of Hb and RBC (left and right, respectively).