Clinical pharmacology and economics of recombinant human erythropoietin in end-stage renal disease

Abstract

The clinical pharmacology of human recombinant erythropoietin (epoetin) was studied in order to compare the effectiveness of various routes and dosing schedules in dialysis patients. Thirty-six patients received epoetin beta three times a week i.v. for at least 12 wk. The mean dose needed to achieve target hemoglobin was 225 +/- 36 U/kg per week (median dose, 180 U/kg per week). Twenty-eight of 36 patients who were converted to a once-a-week i.v. schedule increased their requirements to 429 +/- 50 U/kg per week in order to maintain a target hematocrit of 33 to 40 vol%. Twelve of 28 patients could maintain their target hematocrit when dosed once a week s.c. at 84 +/- 10 U/kg. The other 16 patients required 137 +/- 15 U/kg per week divided into two doses. In the entire group of 28 patients, the weekly requirement for epoetin was reduced by 50% when the s.c. route was used two or three times a week. Pharmacokinetic studies performed during chronic therapy indicated rapid clearance of erythropoietin (t1/2 of 6.8 +/- 0.3 h). Single i.v. doses greater than 150 U/kg were required to increase basal erythropoietin by 30 mU/mL at 44 h postdosing. With s.c. dosing, such increments in erythropoietin levels frequently persisted beyond 60 h because of prolonged and slow absorption. Pharmacokinetic simulations in conjunction with clinical correlation of the erythropoietic response suggest that the duration that the erythropoietin levels are maintained, and not the absolute peaks, is the primary determinant of efficacy. This may result from nonlinearity in the dose response. Pharmacokinetic simulation also indicated that i.v. dosing could not maintain adequate interdialytic erythropoietin levels, whereas s.c. dosing could. Cost analysis indicated that the use of s.c. dosing two or three times a week at an average total weekly dose of 110 to 120 U/kg is effective treatment of anemia in most dialysis patients.

Control of rHuEPO biological activity: The role of carbohydrate

“…Removal of EPO from cell cultures results in apoptosis of erythroid precursor cells [45]. Thus, therapeutically meaningful erythropoiesis requires continuous ligand: receptor-binding events that can occur if the erythropoietic protein has a pharmacokinetic profile allowing maintenance at a serum concentration above the MEC [46]. Slower clearance in vivo results in an increase in relative serum concentration compared to that of a faster-clearing molecule, and the relative concentration differences between slow and fast-clearing molecules will increase with time.…”

Recommendations for anemia treatment in pediatric patients

“…[32][33][34][35] Vários estudos de farmacocinética da AEE evidenciaram maior duração da ação utilizando a via subcutânea e a mesma eficiência, com doses 30% a 50% menores que as intravenosas. [36][37][38][39] A via subcutânea é preferencial para pacientes adultos e pediátricos em quaisquer estágios da DRC, porém, a administração intravenosa é a mais confortável para crianças em hemodiálise (HD). A via intraperitoneal não é recomendada.…”

Exploring dosing frequency and administration routes in the treatment of anaemia in CKD patients

“…Alcorco´n, 28922 Madrid, Spain. Email: jmportoles@fhalcorcon.es the threshold effect and to avoid a decline in the blood levels of erythropoietin below those necessary for the prevention of apoptosis in the bone marrow [10].…”

“…route needs to be given three times a week. A number of studies have shown that reducing the dose frequency to once or twice per week actually requires a 50% increase in concentration of rHuEPO dose [7][8][9]. Indeed, when the drug is given i.v.…”