COMPARISON OF A DIRECT AND INDIRECT POPULATION PHARMACODYNAMIC MODEL - APPLICATION TO RECOMBINANT-HUMAN-ERYTHROPOIETIN IN ATHLETES

Basic physiologic indirect response models have been proposed to accou nt for the pharmacodynamics gf. drugs that act by way of inhibition or stimulation of the production or loss of endogenous substances or med iators. In this work, these models were applied to account for the eff ects of recombinant human erythropoietin (rHuEpo) in man. Indeed, rHuE po induces a delayed increase of serum soluble transferrin receptors ( sTfr) and a delayed decrease in ferritin (fr) concentrations. The purp ose of the present study was to compare two pharmacodynamic approaches to relate serum erythropoietin (Epo) concentrations to the effect of rHuEpo on sTfr, and fr, the ''indirect effect'' and the ''effect compa rtment'' models. However, due to the average lag time of about 50 hr b etween the first intake of rHuEpo and the onset of the measurable effe cts, a delay function was incorporated into the ''indirect response mo dels'' to describe the relationship between the Epo plasma concentrati ons and the endogenous receptors or mediators affected by the drug and responsible for the effects on sTfr and fr. There are no real differe nces in the descriptive features of the two models used. For these rea sons, the indirect model seems more appropriate because it supplies a possible mechanistic interpretation of the physiological process.