2015 Therapeutic Proteins

Mechanisms of Action

• ERYTHROPOIETIN is the most important (but not sole) regulator of the proliferation of committed red blood cell progenitors
  • interacts with erythropoietin receptors on red cell progenitors
  • the erythropoietin receptor is a member of the JAK/STAT superfamily
  • produced in the kidney

• inverse relationship between hematocrit (or hemoglobin) level and serum erythropoietin level
  • exception is in chronic renal failure when erythropoietin levels are low because the kidneys cannot produce the growth factor

Pharmacokinetics

• ERYTHROPOIETIN (rHuEPO, epoetin alfa) is produced in response to severe anemia
  • it has a relatively short half-life: given IV 3-4X per week

• DARBEPOETIN is a more heavily glycosylated form
  • it has 2-3X longer half-life: given weekly

• METHOXY POLYETHYLENE GLYCOL EPOETIN has a covalently attached PEG polymer
  • given IV or SC at 2-week or monthly intervals

Therapeutic Uses

• anemia
  • secondary to chronic kidney disease (particularly effective)
    • nearly all patients will require iron supplementation; some patients may require folate supplementation
  • due to primary bone marrow disorders and secondary anemias

• reduce the need for transfusion in high-risk surgical patients
  • after phlebotomies for autologous transfusion

• iron overload (hemochromatosis)

• M-PEG-epoetin should not be used in patients with anemia due to cancer chemotherapy (clinical trial found significant increase in deaths)

• banned by the International Olympic Committee (increased red blood cell concentration may increase oxygen delivery to muscles and improve performance)

Side effects

• Pitfalls
• Side effects
• Hematopoietic agents
  • Erythroid growth factors
  • Myeloid growth factors
  • Megakaryocyte growth factors