The Primary Goal of Project 3 is to establish more effective treatment of anemia in critically ill infants,who receive multiple red blood cell (RBC) transfusions and who, as a result, face increased risk ofinfections and other complications. We propose to reduce the number of transfusions by optimizing theuse of erythropoietin (r-HuEPO). The extent to which this can be accomplished will be determined usingpharmacokinetic (PK) and pharmacodynamic (PD) data from anemic, neonatal infants undergoing RBCtransfusions supplemented with data from PK/PD experiments in neonatal sheep. Our overallhypothesis is that treatment of neonatal anemia can be improved by optimizing administration of r-HuEPO through a comprehensive knowledge of the physiology of erythropoiesis and EPO's complexPK/PD behavior.
Aim 1 is to identify the PK/PD and physiologic factors important in predicting andmaximizing r-HuEPO's erythropoietic effect based on PK/PD studies of anemic infants and neonatal sheep.
Aim 2 is to make Bayesian population PK/PD efficacy predictions of r-HuEPO in anemic infantsby applying allometric and physiologic scaling and a physiologic-mechanistic PK/PD model developedfrom the data generated in Aim 1.
Aim 3 is to predict the extent to which r-HuEPO's effect (i.e.reduction/elimination of RBC transfusions) can be maximized through an optimal dosing design basedon Bayesian Markov Chain Monte Carlo simulations of human clinical trials using the PK/PD modeldeveloped in Aim 2.
Aim 4 is to validate a safe, non-radioactive r-HuEPO tracer (BioEPO) for use inmechanistic PK/PD studies in sheep and humans. Important physiologic and pharmacologic issuesrelated to neonatal anemia that cannot be elucidated by current methods can be resolved if a safe andeffective BioEPO tracer is developed. Project 3 will test 4 hypotheses: 1) Endogenous EPO productionrate and plasma level vs. time profiles relate in a predictable manner to changes in hemoglobin vs. timeprofiles; 2) EPO receptor (EPOR) pool size changes in a predictable way with changes in the degree ofanemia and with the degree of exposure to r-HuEPO and EPO; 3) Stress erythropoiesis results in areduction in the reticulocyte mean residence time in peripheral blood due to reticulocytes beingreleased from the bone marrow in a more mature form; 4) Using an optimized r-HuEPO dosing regimenit is possible to significantly reduce the number of RBC transfusions in lamb experiments designed tomimic transfusion practices in neonatal anemia. We intend to achieve our Primary Goal by amechanism and model-based approach assisted by powerful tracer methodologies, and through theuse of advanced, modern drug development tools such as Bayesian analysis and clinical trialsimulations. Our PK/PD analysis will extend the latest developments in receptor-mediated PK/PDanalysis and will consider processes taking place on the cellular and receptor level, including anemia-dependentchanges that affect the life-span of reticulocytes and RBCs during stress erythropoiesis. Wewill make use of advanced 125-l-r-HuEPO tracer kinetic methodologies to address Aim 1 and enableelucidation of the factors that impact the efficacy and utility of r-HuEPO for achieving the Primary Goal.Project 3 will interact synergistically with Project 1 and the Core Facility in several key areas of mutualinterest, e.g. investigation of RBC volume and RBC life-span and mathematical modeling of the survivalof biotinylated RBCs. The Primary Goal in this project and the collaborative work Dr. Veng-Pedersenwill provide on Project 1 follow the current trend in clinical practice to reduce the number of neonataltransfusions and support our PPG's theme of optimizing the transfusion management of anemicnewborn infants.
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