A SYSTEM APPROACH TO PHARMACODYNAMICS - PLASMA IRON MOBILIZATION BY ENDOGENOUS ERYTHROPOIETIN IN THE SHEEP FETUS - EVIDENCE OF THRESHOLD RESPONSE IN SPONTANEOUS HYPOXEMIA

At present, nearly all infants with birth weights of < 1 kg receive bl ood transfusions for treatment of clinical signs of tissue hypoxia res ulting from anemia of prematurity. In contrast to the successful use o f recombinant human erythropoietin (rhEp) in adults, treatment of anem ic neonates with rhEp to stimulate red cell production and reduce the need for transfusions that pose serious infectious and immunologic ris k has not been effective. The present study investigates the pharmacod ynamics (PD) of endogenous erythropoietin (Ep) in sheep fetuses to det ermine possible causes for the poor rhEp response in early development . The dynamic relationship between plasma Ep and plasma iron resulting from spontaneous hypoxemic episodes is investigated by PD system anal ysis. The erythropoietic effect of Ep is measured in terms of the mobi lization of plasma iron needed in the production on new erythrocytes. A hysteresis minimization approach is employed to determine the intrin sic PD dose-response relationship (transduction) of Ep. The dose-respo nse relationship shows a well-defined threshold level that has to be e xceeded before Ep begins to show a significant effect on plasma iron. It is postulated that the threshold mechanism may serve a useful purpo se during early development by reducing the risk of the fetus developi ng a pathological degree of polycythemia and hyperviscosity in the rel atively hypoxemic fetal environment. At the same time, the threshold s erves the purpose of providing a needed response to more severe pathol ogic hypoxemic episodes. The occurrence of anemia during subsequent po stnatal life when PaO2 levels increase markedly may be the inevitable, but unfortunate corollary of a continuation of this mechanism. If the poor response to rhEp in early neonatal life is due to a threshold me chanism, then it will be necessary to administer Ep at significantly l arger dosing rates to ensure a sufficient and sustained coverage above the threshold level.