EPIAO Mechanism of Action

Pharmacology: Male SD rats with induced chronic renal failure (CRF) were treated either with Epiao or Epogen (Amgen) at the same dosage. The anemic state associated with these animals was significantly (p<0.01) corrected, irrespective of the source of the erythropoietin (p>0.05). However, Epiao therapy could not improve renal function, nor histological changes were corrected, except glomerulus capillary blood vessel cluster proliferated, and the number of red blood cells in the vessels increased.
Epiao can stimulate erythropoiesis in anemic patients with CRF, including both patients on dialysis and those who do not require dialysis. The first evidence of a response to the 2 or 3 times weekly administration of Epiao is an increase in the reticulocyte count within 10 days, followed by increases in the red cell count, hemoglobin and hematocrit, usually within 2-6 weeks. Because of the length of time required for erythropoiesis several days for erythroid progenitors to mature and be released into the circulation, a clinically significant increase in hematocrit is usually not observed in <2 weeks and may require up to 6 weeks in some patients. Once the hematocrit reaches the target range (30-36%), that level can be sustained by Epiao therapy in the absence of iron deficiency and concurrent illnesses.
The rate of hematocrit increase varies among patients and is dependent upon the dose of Epiao, within a therapeutic range of approximately 50-300 u/kg 3 times weekly.
A greater biologic response is not observed at doses exceeding 300 u/kg 3 times weekly. There are other factors affecting the rate and extent of response eg, availability of iron stage, baseline hematocrit and the presence of concurrent medical problems.
Pharmacokinetics: Serum rh EPO Concentration: Healthy Men: After IV administration of epoetin alfa 300 iu to 7 healthy male adults, 2 half-life times of serum Epiao are achieved at 0.4 and 7 hrs separately after its peak level.
Hemodialysis (HD) Patients with Renal Failure: After IV administration of epoetin α 300 iu to 11 HD patients with renal failure, the serum epoetin α concentration showed the same variation tendency as that of healthy men with the half-life of 6 hrs.
The half-life of serum epoetin α is 5.9 hrs when 8 people received epoetin α 1500 iu IV, and 7.5 hrs for 3000 iu IV (12 people). The elimination time of epoetin α prolongs a little when the dose is increased.
Urine Excretion: 24 hrs later after IV administration of epoetin α 300 iu to 7 healthy volunteers, 0.88% of the dose was excreted in the urine.
Toxicology: Preclinical Safety Data: The LD₅₀ of epoetin α in mice when administered either IV or SC are >1 x 10⁶ u/kg, which is >6700 times of the regular clinical dose and 3,330 times of the maximum clinical effective dose.
There were no irreversible changes observed in systemic examination during long-term (4-5 weeks) toxicity studies in rats and dogs treated with up to 1000 u/kg daily of Epiao. No effect of recombinant erythropoietin on reproduction system, mutagenic potential and oncogenic/carcinogenic potential have been documented, nor observed with Epiao.