Deicher Robert, Hörl Walter H
Division of Nephrology and Dialysis, Department of Medicine III, University of Vienna, Vienna, Austria.
Drugs. 2004;64(5):499-509. doi: 10.2165/00003495-200464050-00004.
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.
内源性促红细胞生成素（EPO）由一个中央多肽核心组成，该核心被翻译后连接的碳水化合物所覆盖。目前可用的四种促红细胞生成刺激剂（ESA）中的三种——α-促红细胞生成素、β-促红细胞生成素和ω-促红细胞生成素——由相同的氨基酸序列组成，但由于生产过程中类型和宿主细胞特异性的差异，糖基化有所不同。α-促红细胞生成素和β-促红细胞生成素在分子特征和药代动力学数据方面彼此相似，尽管β-促红细胞生成素的分子量较高，唾液酸化聚糖残基数量较少，并且可能具有一些轻微的药代动力学优势，例如更长的末端消除半衰期。长期使用ESA的一个严重不良反应是纯红细胞再生障碍。这种效应主要在从制剂中去除白蛋白后在美国境外生产的α-促红细胞生成素皮下使用时观察到。与静脉途径相比，一些研究报告称皮下注射促红细胞生成素具有剂量节省效应。β-促红细胞生成素一直是旨在证明减少给药频率有效性的研究对象，但结果并不明确。ω-促红细胞生成素是在与所有其他促红细胞生成剂不同的宿主细胞中产生的，因此糖基化和药代动力学有所不同。小规模临床研究发现ω-促红细胞生成素比α-促红细胞生成素稍强。δ-促红细胞生成素是一种最近获批的药物，由经过基因工程改造的人类细胞产生，这些细胞在新引入的调控DNA序列的控制下转录和翻译EPO基因。然而，δ-促红细胞生成素尚未上市，可用数据很少。促红细胞生成素类似物α-达贝泊汀带有两个额外的糖基化位点，允许更高程度的糖基化。因此，与其他促红细胞生成素相比，α-达贝泊汀具有更长的血清半衰期和更高的相对效力，随着给药间隔的延长，效力会进一步增加。α-达贝泊汀的剂量需求在静脉和皮下给药途径之间似乎没有差异。与其他促红细胞生成素相比，α-达贝泊汀给药频率较低，从长远来看可能会降低药物成本，但单个患者所需的剂量或给药频率变化很大。进一步的研究应旨在确定促红细胞生成剂个体需求的预测因素，从而使肾病学家能够开出具有成本效益的个体化治疗方案。
