Differentiating factors between erythropoiesis-stimulating agents: a guide to selection for anaemia of chronic kidney disease

Abstract

Endogenous erythropoietin (EPO) consists of a central polypeptide core covered by post-translationally linked carbohydrates. Three of the four currently available erythropoiesis stimulating agents (ESA)--epoetin-alpha, epoetin-beta and epoetin-omega- are composed of an identical amino acid sequence, but glycosylation varies as a result of type- and host cell-specific differences in the production process. Epoetin-alpha and epoetin-beta resemble each other with respect to molecular characteristics and pharmacokinetic data, although epoetin-beta has a higher molecular weight, a lower number of sialylated glycan residues and possibly slight pharmacokinetic advantages such as a longer terminal elimination half-life. A serious adverse effect of long-term administration of ESA is pure red cell aplasia. This effect has been observed predominantly with subcutaneous use of epoetin-alpha produced outside the US after albumin was removed from the formulation. In comparison with the intravenous route, subcutaneous administration of epoetin has been reported to have a dose-sparing effect in some studies. Epoetin-beta has been the subject of studies aimed at proving efficacy with a reduced administration frequency but results are not unequivocal. Epoetin-omega is produced in a different host cell than all other erythropoietic agents, hence glycosylation and pharmacokinetics are different. Small-scale clinical studies found epoetin-omega to be slightly more potent than epoetin-alpha. Epoetin-delta is a recently approved agent produced by human cells that are genetically engineered to transcribe and translate the EPO gene under the control of a newly introduced regulatory DNA sequence. However, epoetin-delta is not yet on the market and few data are available. The erythropoietin analogue darbepoetin-alpha carries two additional glycosylation sites that permit a higher degree of glycosylation. Consequently, in comparison with the other epoetins, darbepoetin-alpha has a longer serum half-life and a higher relative potency, which further increases with extension of the administration interval. Dosage requirements of darbepoetin-alpha do not appear to differ between the intravenous and subcutaneous routes of administration. The less frequent administration of darbepoetin-alpha in comparison to the other epoetins may reduce drug costs in the long term, but the variability in dosage or dosage frequency required within a single patient is high. Further studies should be aimed at defining predictors of the individual demand for erythropoietic agents, thereby allowing nephrologists to prescribe a cost-effective, individualised regimen.