Erythropoietin receptor agonists

Predicting the Outcome of Phase I Studies of Erythropoietin Receptor Agonists... 

In this case study a simulation strategy, based on a mechanistic PK/PD model, was developed to predict the outcome of the first time in man (FTIM) and proof of concept (POC) study of a new erythropoietin receptor agonist (ERA). A description of the erythropoiesis model, along with the procedures to scale the pharmacokinetics and pharmacodynamics based on preclinical in vivo and in vitro information is presented. The Phase I study design is described and finally the model-based predictions are shown and discussed. 

Phage display of random peptide libraries identified agonists of erythropoietin receptor... 

Epoetin alfa Agonist of erythropoietin receptors expressed by red cell progenitors Stimulates erythroid proliferation and differentiation, and induces the release of reticulocytes from the bone marrow Treatment of anemia, especially anemia associated with chronic renal failure, HIV infection, cancer, and prematurity prevention of the need for transfusion in patients undergoing certain types of elective surgery IV or SC administration 1-3 times per week Toxicity Hypertension, thrombotic complications, and, very rarely, pure red cell aplasia to reduce the risk of serious CV events, hemoglobin levels should be maintained < 12 g/dL... 

Fig. 2.1 Crystal structure of a complex of the extracellular domain of the human erythropoietin receptor (EBP) and an agonist peptide, the EPO-mimetic peptide 1 (EMPl).

C27H31N5O6 521.572 Selective adenosine A2-receptor agonist. Enhances serum erythropoietin levels in hypoxic (polycythaemic) mice. 

The pathway is negatively regulated by protein tyrosine phosphatases and by feedback inhibition through STAT-mediated expression of suppressors of cytokine signaling (SOCs). Agonists for cytokine receptors are currently used to stimulate red blood cell maturation in anemia (erythropoietin) and to stimulate the immune system (interferons). The cascade nature of the cytokine pathway lends itself to future agents that specifically target components of the pathway. 

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