Multidose optimization simulation of erythropoietin treatment in preterm infants

Abstract

Introduction: Preterm infants commonly develop anemia requiring red blood cell transfusions (RBCTx). Although an alternative therapy is recombinant human erythropoietin (Epo), it is not widely employed. To provide a rigorous scientific basis supporting the latter approach, a model-based simulation analysis of endogenous erythropoiesis was developed.

Results: The pharmacodynamic/pharmacokinetic (PK/PD) model identified an optimal Epo dosing algorithm in preterm infants that demonstrated maximal efficacy when Epo was dosed frequently during the early weeks of life (when phlebotomy loss is greatest). Model-based simulations employing optimized Epo dosing predicted that 13 of the 27 (46%) infants would avoid RBCTx ("good responders"). Importantly, simulation results identified five subject-specific covariate factors predictive of good Epo response.

Discussion: This simulation study provides a basis for possibly eliminating RBCTx in infants who can be selected for optimized Epo therapy.

Methods: Epo PD hemoglobin production parameters were determined in 27 preterm infants studied intensively during the first 28 d of life. Model-derived Epo PD parameters were combined with PK parameters derived from the literature to simulate an optimized intravenous Epo bolus dosing schedule. The goal of this simulated optimized schedule was to eliminate RBCTx, as prescribed per current guidelines, in as many preterm infants as possible.

Figure 1

Erythropoietin (Epo) dosing profile. Simulated Epo doses administered to 27 preterm infants optimized to eliminate alloimmune red blood cell transfusions. All simulated epo doses were 600 U/kg intravenous bolus doses. the dosing times for the first and second doses were so close as to effectively represent a double dose. the same is the case for the tenth and eleventh doses.

Figure 2

Erythropoietin (Epo) plasma concentration profile. Simulated plasma Epo concentration profile for an infant, corresponding to the simulated, optimized Epo dosing administered to 27 preterm infants shown in Figure 1. The Epo dosing was optimized to avoid red blood cell transfusions in the infants.

Figure 3

Simulated Hb profile from erythropoietin (Epo) dosing. Simulated infant Hb curves based on the optimized Epo dosing shown in Figure 1. Data required to perform these simulations included Hb concentration at birth, the phlebotomy loss throughout the first 28 d of life, individual pharmacodynamic parameters, and population pharmacokinetic parameters. The solid line is the infant’s simulated Hb, the dashed staircase line is the red blood cell transfusion trigger criteria based on the PINt trial (12), and the dashed increasing line is the cumulative amount of blood removed from the infant as a result of physician-ordered laboratory tests. subjects a and b were “good Epo responders” predicted to avoid transfusions, in contrast to subjects c and d, who were “poor Epo responders” who would have needed a transfusion at the transfusion trigger crossing point (dark circle).