Renogen Mechanism of Action

Pharmacology: Pharmacodynamics: Chronic Renal Failure Patients: The level of tissue oxygenation normally regulates endogenous production of erythropoietin. Hypoxia and anemia generally increase the production of erythropoietin which in turn stimulates erythropoiesis. In normal subjects, plasma erythropoietin levels range from 0.01 to 0.03 units/mL and increase up to 100 to 1000 fold during hypoxia or anemia. In contrast, in patients with chronic renal failure (CRF), production of erythropoietin is impaired, and this erythropoiet in is the primary cause of their anemia.
The clinical situation where there is a progressive and usually irreversible decline in kidney function is chronic renal failure (CRF). Renal dysfunction, including anemia, with or without regular dialysis can be manifested in some patients. Those patients with CRF who require regular dialysis or dialysis or kidney transplantation for survival are patients with end-stage renal disease (ESRD). Epoetin alpha stimulates erythropoiesis in anemic patients with CRF for both patients requiring dialysis or Epoetin alpha not.
An increase in the reticulocyte count within 10 days, followed by increases in the red cell count hemoglobin, and hematocrit is the first evidence of a response to Epoetin alpha treatment of three times weekly administration of the drug. Because of the length of time required for erythropoiesis which is several days for erythroid progenitors to mature and be released into the circulation, it will take at least 2-6 weeks for a clinically significant increase in hematiocrit level. Upon reaching the suggested target range (30%-36%) for hematocrit increase. Epoetin alpha can sustain that level in the absence of iron deficiency and concurrent illnesses.
that level in the absence of iron deficiency and concurrent illnesses.
Hematocrit increase varies between patients and is dependent upon the dose of Epoetin alpha with the given therapeutic range of approximately 50 to 300 units/kg three times weekly. If the dose exceeds 300 units/kg three times weekly, a greater biologic response is not observed. The baseline hematocrit, availability of iron stores and the presence of concurrent medical problems are other factors that can affect the rate and extent of response.
Zidovudine-treated HIV infected patients: Epoetin alpha response in HIV-infected patients is dependent upon the endogenous serum erythropoietin level prior to treatment. Patients with endogenous serum erythropoietin level ≤0.5 units/mL and who are receiving a dose of zidovudine ≤ 420 mg/week, may respond to Epoetin alpha therapy. Patients with endogenous serum erythropoietin levels > 0.5 units/mL do not appear to respond to Epoetin alpha therapy. In a series of four clinical trials involving 255 patients, 60% to 80% of HIV-infected patients treated with zidovudine had endogenous serum erythropoietin levels ≤ 0.5 units/mL. Reduced transfusion requirements and increased hematocrit are manifestations of a response to Epoetin alpha in Zidovudine-treated HIV-patients.
Cancer patients on Chemotherapy: Concomitant use of chemotherapeutic drug can cause anemia in cancer patients. Epoetin alpha has been shown to increase hematocrit and decrease transfusion requirements after the first month of therapy (months 2 and 3), in anemic cancer patients undergoing chemotherapy.
A series of clinical trials involved 131 anemic cancer patients who were receiving cisplatin or non-cisplatin containing chemotherapy. Endogenous baseline serum erythropoietin levels varied among patients in these trials with approximately 75% (n = 83/110) having endogenous serum erythropoietin levels > 0.5 units/mL. In general, patients with lower baseline serum erythropoietin levels responded more vigorously to Epoetin alpha than patients with higher baseline erythropoietin levels. Although no specific serum erythropoietin level can be stipulated above which patients would unlikely to respond to Epoetin alpha therapy. Treatment of patients with grossly elevated serum erythropoietin levels (e.g. >0.2 units/mL) is not recommended.
Pharmacokinetics: Epoetin alpha administered intravenously is eliminated at a rate consistent with first order kinetics. Half-life of Epoetin alpha in patients with chronic renal failure ranges from 4 to 13 hours. Generally after 24 hours of administration of Epoetin alpha, plasma levels return to their baseline levels. After subcutaneous administration of Epoetin alpha, peak serum levels are achieved within 5 to 24 hours after administration, and decline more slowly thereafter.
In healthy volunteers, half-life after intravenous administration is 20% shorter than the one observed for chronic renal failure patients. Recombinant human erythropoietin is available only for injection. The onset of response has been reported to occur as early as 7 days. However, some patients may require as long as 6 weeks of treatment to achieve optimal effect. Peak serum levels occur within 5 to 24 hour after subcutaneous administration and decrease slowly.
Measurable plasma levels of Epoetin alpha are sustained for at least 24 hours. Recombinant human erythropoietin is extracted from plasma by erythroid precursors. It is eliminated via first-order kinetics with circulating half-life of 4 to 13 hours after intravenous administration in patients with CRF. The half-life in healthy adults is 20% shorter than in CRF patients.
Subcutaneous administration results in a prolonged half-life between patients with CRF not on dialysis and those maintained on dialysis. The pharmacokinetics of Epoetin alpha in children and adolescents appear similar to those of adults. Phamacokinetics data in neonates is limited. In children on continuous ambulatory peritoneal dialysis (CAPD), Epoetin alpha is sometimes administered by the intraperitoneal route in order to avoid the psychological distress associated with subcutaneous administration.
A study by Kausz colleagues evaluated the efficacy and Pharmacokinetics of intraperitoneal Epoetin alpha in eight children. A single dose of 100 units/kg in 50 mL of dialysate was administered into a dry peritoneal cavity after nightime dialysis. Relative bioavailability was similar to subcutaneous dosing. Patients maintained a normal hematocrit level with an intraperitoneal Epoetin dose that was similar to their previous subcutaneous dose.