ERYTHROPOEITIN PHYSIOLOGY AND PHARMACOLOGY IN INFANTS

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The many red blood cells (RBC) transfusions administered to preterm infants as treatment for anemia are expensive and pace them at risk for blood-borne infections and other transfusion related complications. The long-term objectives of Project #1 is to develop effective strategies for optimally administering recombinant human erythropoietin (r-HuEPO) in the treatment of anemia of prematurity. Achieving this goal is important and timely because r-HuEPO remains an evolving clinical therapy without a clear consensus of how, when and for whom it should be used in these patients. Our objective will be accomplished by performed mechanistically based EPO pharmacokinetic (PK) and pharmacodynamic (PD) studies in sheep and human subjects using sensitive and accurate tracer methodologies. Achieving maximal stimulation for erythropoiesis relies in part upon developing a comprehensive understanding of EPO's thus far elusive in vivo metabolism and relies in part upon developing a comprehensive understanding of EPO's thus far elusive in vivo metabolism and its complex PK and PD behaviors. Because plasma EPO concentrations in anemic preterm infants are reduced relative to those in anemic adults, inadequate EPO production has been suggested as a primary underlying mechanism for the anemia these neonates inevitably develop and as justification for r-HuEPO treatment. Based on direct animal and indirect human data, we suggest that inadequate EPO production is not the primary on direct animal and indirect human data, we suggest that inadequate EPO production is not the primary mechanism, but that other mechanisms may be more important. The basis for this speculation is an expanding body of data indicating that EPO's in vivo disposition occurs primarily via a saturable, receptor-mediated process. As an overall hypothesis we speculate that EPO's in vivo PK and PD are determined by the number and affinity of EPO receptors (EPO-R's) located predominantly on the body's expandable pool of erythroid progenitor cells. This hypothesis is consistent with the observation that EPO's PK behavior is non-linear, that EPO elimination is 3 to 4 times greater in premature infants than adults, and that the red marrow occupies a 3- to 4-fold greater volume per kg body weight in young children than adults. Because of their sensitivity and accuracy, PK methodologies utilizing labeled EPO tracers are ideally suited for investigating EPO's non-linear behavior and for directly measuring its endogenous production rate. In addressing our proposal's three aims, 125I-r-HuEPO and biotinylated r- HuEPO and biotinylated r-HuEPO (Bio-EPO) will be administered as tracers in advanced system analysis-based PK and PD studies performed in sheep and humans, respectively. In Aim #1, methods for analysis-based PK and PD studies performed in sheep and humans, respectively. In Aim #1, methods for biotinylating r-HuEPO retaining its PK behavior and for measuring Bio-EPo in tracer amounts will be developed and validated. In Aims #2 and #3, 125I-r-HuEPO tracer methodology will first be applied in vivo experiments in sheep to determine the effect of perturbations in erythropoiesis (i.e., by bone marrow ablation and by phlebotomy-induced anemia and r-HuEPO treatment) on EPO's PK, PD, and production rate. When Bio-EP becomes available as a tracer, similar studies will be conducted in human infant and adult study groups. Knowledge gained about EPO's PK and PD will permit more optimal use of r-HuEPO thus leading to a reduction in the multiple RBC transfusions typically recovered by preterm infants.