Efficacy Comparison of Intravenous and Subcutaneous Recombinant Human Erythropoietin Administration in Hemodialysis Patients

Bommer, Jürgen; Barth, Heidi; Zeier, M; Mandelbaum, A.; Bommer, Gudrun; Ritz, Eberhard; Reichel, Hans; Novack, Roger L.

doi:10.1159/000419523

Cited by 64 publications

(28 citation statements)

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“…In Europe and the USA, many clinical studies comparing intravenous and subcutaneous injections revealed that subcutaneous injection of rHuEPO is more advantageous than intravenous injection in terms of the improvement in anemia and its long-lasting effect, as well as costeffectiveness [64][65][66][67][68][69][70][71][72][73][74][75][76][77]. In the conventional European and US guidelines on therapy for renal anemia [78,79], subcutaneous injection was also recommended for HD patients.…”

Section: (2)target Hb Levels To Be Maintained In Pd Patientsmentioning

confidence: 99%

2015 Japanese Society for Dialysis Therapy: Guidelines for Renal Anemia in Chronic Kidney Disease

Yamamoto¹,

et al. 2017

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Section: (2)target Hb Levels To Be Maintained In Pd Patientsmentioning

confidence: 99%

2015 Japanese Society for Dialysis Therapy: Guidelines for Renal Anemia in Chronic Kidney Disease

Yamamoto¹,

et al. 2017

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“…Despite the apparent low bioavailability, s.c. administration of rHuEPO produces equivalent efficacy to i.v. administration, and this is assumed to be due to the prolonged absorption leading to reduced receptor saturation (Kampf et al, 1989;Bommer et al, 1991). Absorption rates of rHuEPO vary according to the administration site, most likely reflecting regional differences in blood and lymph flow (Jensen et al, 1994).…”

mentioning

confidence: 99%

Lymphatic Absorption Is the Primary Contributor to the Systemic Availability of Epoetin Alfa following Subcutaneous Administration to Sheep

McLennan¹,

Porter²,

Edwards³

et al. 2004

J Pharmacol Exp Ther

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The contribution of the lymphatics to the absorption and systemic availability of recombinant human epoetin alfa (rHuEPO) following s.c. injection was examined using a cannulated sheep model. Parallel studies were conducted in sheep where a single bolus dose was administered either by i.v. (10, 100, or 1000 IU/kg) or s.c. (400 IU/kg) injection. The first s.c. group served as a control for the calculation of absolute bioavailability. In the second group, the efferent popliteal lymphatic duct was cannulated and peripheral lymph draining the injection site was continuously collected. In the third group, the thoracic duct was cannulated to allow collection of central lymph just prior to entry into the systemic circulation. Blood was periodically sampled from all animals, and concentrations in serum and lymph were determined by enzyme-linked immunosorbent assay. The cumulative amount of rHuEPO recovered in peripheral and central lymph was 83.9 Ϯ 6.6% and 75.3 Ϯ 3.9% of the administered dose, respectively, indicating almost complete absorption from the s.c. injection site and minimal clearance during transit through the lymphatic system. After i.v. administration, the systemic clearance of rHuEPO decreased with increasing dose, reflecting capacity-limited elimination kinetics. A pharmacokinetic model was developed to simultaneously fit experimental data for all treatment groups and estimate bioavailability. The direct measurement of Ͼ75% of the dose in peripheral and central lymph independently verifies the calculated bioavailability of 87% and demonstrates the major role of the lymphatic route in the overall s.c. bioavailability of rHuEPO after s.c. administration with this animal model. Erythropoietin (EPO) is a renally synthesized 30.4-kDa glycoprotein involved in the regulation of red blood cell proliferation and differentiation. Recombinant human epoetin alfa (rHuEPO) has been extensively utilized in the treatment of anemia associated with chronic renal failure, AIDS, and chemotherapy.Pharmacokinetic studies of rHuEPO have demonstrated dose-dependent disposition in humans (Flaharty et al., 1990;Veng-Pedersen et al., 1995), monkeys (Ramakrishnan et al., 2003), sheep (Veng-Pedersen et al., 1999), and rats (Kato et al., 1997) after i.v. administration. In these studies, nonlinear kinetics were characterized by decreased clearance with increasing dose. Although the exact elimination pathway has not been fully elucidated, studies comparing clearance (CL), mean residence time (MRT), and terminal half-life (t 1/2 ) preand postablation of the bone marrow in sheep, have provided significant evidence that elimination occurs predominantly in the bone marrow (Chapel et al., 2001). The capacity-limited CL is likely to be a receptor-mediated endocytosis by erythroid progenitor cells and has been described previously using a Michaelis-Menten-type elimination (Kato et al., 1997;Veng-Pedersen et al., 1999;Ramakrishnan et al., 2003). Although EPO receptors appear to have an important role in the distribution of EPO outside...

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“…Although the prolonged presence of high serum EPO levels after SC rHuEPO injection do not necessarily indicate a sustained stimulatory effect on the bone marrow, recent clinical studies suggest that the rHuEPO requirement is less with the same dose given by the SC compared with the IV route [14,15]. Our experience suggests that a single SC dose of 150 units rHuEPO/kg applied once a week is sufficient to produce and maintain the required target haemoglobin levels in most children with CRF [10].…”

Section: Discussionmentioning

confidence: 99%

“…This route may be preferable to the IV route, allowing less frequent application and injections at home. In adults with CRF maintained on SC rHuEPO, the drug appears to be more effective than when given IV, despite the lower bioavailability [11,13,15,16]. For children, SC administration appears to be of special benefit in preterminal CRF and during continuous ambulatory peritoneal dialysis (CAPD) [4,9], where a permanent vascular access is not available.…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetics of recombinant human erythropoietin applied subcutaneously to children with chronic renal failure

et al. 1993

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Abstract. The single-dose pharmacokinetics of recombinant human erythropoietin (rHuEPO) given SC was investigated in 20 patients aged 7-20 years at different stages of chronic renal failure. In a pilot study we confirmed the lower bioavailability of the drug in 2 children when given SC compared with the IV route (24% and 43%, respectively). Following administration of 4,000 units/m2, rHuEPO SC effective serum erythropoietin concentrations increased from a mean baseline level (_+ SD) of 23 ___ 13 units/1 to a mean peak concentration of 265 _+ 123 units/l, which was reached after 14.3 ___ 9.4 h, followed by a slow decline until baseline values were attained at 72 h. Mean residence time was 30 +9 h and mean elimination halftime 14.3 +7 h. The single-dose kinetics of SC rHuEPO in children with different degrees of renal failure are comparable to those in adult patients. Possibly, the higher efficacy of SC rHuEPO in patients with renal anaemia compared with IV rHuEPO is related to its prolonged action.

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Efficacy Comparison of Intravenous and Subcutaneous Recombinant Human Erythropoietin Administration in Hemodialysis Patients

Cited by 64 publications

References 0 publications

2015 Japanese Society for Dialysis Therapy: Guidelines for Renal Anemia in Chronic Kidney Disease

2015 Japanese Society for Dialysis Therapy: Guidelines for Renal Anemia in Chronic Kidney Disease

Lymphatic Absorption Is the Primary Contributor to the Systemic Availability of Epoetin Alfa following Subcutaneous Administration to Sheep

Pharmacokinetics of recombinant human erythropoietin applied subcutaneously to children with chronic renal failure

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