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Choice of erythropoiesis stimulating agent in ESRD
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Introduction
There are currently four FDA (Food and Drug Administration) approved erythropoiesis stimulating agents (ESAs) for use in end-stage renal disease (ESRD) patients in the U.S. They are epoetin alfa (Epogen, Procrit) , darbepoetin alfa (Aranesp), methoxy polyethylene glycol-epoetin beta (Mircera) and peginesatide (Omontys). However, methoxy polyethylene glycol-epoetin beta is not currently available in the U.S. because of patent issues, and pegnisitide is not currently available because of safety issues (see below). For patients with chronic kidney disease (CKD) not on dialysis, both epoetin alfa and darbepoetin alfa are available options. In this article, we will consider whether there are specific properties of the individual ESAs that might make one or another preferred for use in ESRD.
First, a note on terminology and one on upcoming developments that may prove to be important. Until 2012, the only approved ESAs were erythropoietin analogs. In March 2012, peginesatide, a synthetic pegylated peptide with no sequence homology to erythropoietin, received FDA approval in the U.S. for the treatment of anemia of chronic kidney disease in adult patients undergoing dialysis. This novel agent is the first ESA that is not an erythropoietin analog. In March of this year, however, drugmaker Affymax recalled peginesatide (Omontys) from the market after three dialysis patient deaths were linked to hypersensitivity reaction to the drug. At this writing, Affymax was working with FDA officials to try and identify the cause of the severe reactions.
As to timing, available ESAs are likely to change in 2014. Expiration of certain patents will open the ESA market in the United States; it is likely that two or more newer agents may become available.
Efficacy and safety
The ESA class of drugs has been tested for efficacy and safety. It should however, be noted that much of the focus has been comparing the use of these agents to target different hemoglobin (Hb) levels. With that proviso, it can probably be concluded that all of the current ESAs are effective for increasing Hgb concentration and probably reducing transfusion requirements and symptoms related to anemia. Demonstration of efficacy related to higher level patient outcomes has not been established. There has been no demonstration that one ESA is more effective than others. The efficacy profile of peginesatide has been recently shown to be similar to that of older ESAs. 1,2
The safety of ESAs has been a subject of much deliberation in recent years. From the earliest studies it has been clear that there is risk for an increase in blood pressure, and this needs to be managed during therapy. 3 There is no clear evidence that any particular ESA carries greater hypertensive risk. In recent years, a series of studies have indicated that ESAs, when used to target Hgb concentrations greater than 13 g/dL, increase risk for cardiovascular adverse events. 4, 5, 6 The mechanism for harm remains unclear; it could be the result of targeting a higher Hgb, high ESA doses, or some undetermined cause. 7 The cardiovascular safety issue is probably a class effect; it appears that the safety of currently marketed ESAs is probably similar.
Although rare, the formation of antibody-mediated pure red-cell aplasia (PRCA) has been described with both epoietin and darbepoeitin alfa. 8,9 Since peginesatide has no sequence homology to erythropoietin, 10 the Kidney Disease: Improving Global Outcomes (KDIGO) Anemia Work Group recently recommended using peginesatide to treat patients with antibody-mediated PRCA. 11 Since peginesatide is currently not on the market, this will require compassionate use.
Serum half-life
The most clearly defined difference between ESAs is serum half-life. For example, while epoetin alfa has a serum half life of approximately eight hours, methoxy polyethylene glycol-epoetin beta (available outside the U.S. at the time of this writing), has a half-life of approximately 130 hours. Longer half-life suggests the possibility of less frequent dose administration. In the U.S., epoetin alfa is indicated for administration thrice weekly. In hemodialysis units, this is the dose frequency that is most frequently employed. Darbepoetin alfa is indicated once every 1-4 weeks, although most dialysis use appears to be once every one to two weeks. Peginesatide, when on the market, was indicated for once monthly administration to hemodialysis patients (see Table 1).
Less frequent dosing of ESAs is clearly an advantage for non-dialysis CKD and home dialysis patients. There has been more controversy regarding whether less frequent dose administration is an important benefit for in-center hemodialysis patients. Since most injections for these patients are through dialysis lines and, therefore, not painful, and since most patients are in the dialysis unit for treatment three times weekly, it can be argued that it is reasonable to inject an ESA thrice weekly. The main counter argument is that such frequent dosing places a substantial burden on nursing time. Since administration of the ESA takes approximately two minutes per patient, and a common nursing responsibility is 12 patients per shift, 24 minutes of a dialysis shift may be spent injecting ESAs. 12,13 This would seem to be suboptimal since nurses play a critical role in patient care, assessment, and education. Separate studies by Schiller et al. and Saueressig et al. both estimated that conversion to a once monthly ESA would reduce nursing ESA administration time by approximately 80%. 12, 13
Another advantage of longer serum half life is the impact on any differential effect between intravenous and subcutaneous dosing. For example, when a short acting agent epoetin alfa is administered subcutaneously, overall dose requirements are lower. 14 This is probably due to injected erythropoietin that never actually interacts with the erythropoietin receptor before being metabolized. As a result, in order to reduce the total cost of anemia care, many dialysis units choose to administer epoetin alfa by the subcutaneous route. 15 For the hemodialysis patient this means uncomfortable skin injections, despite intravenous access being readily available. For darbepoetin alfa and peginesatide, having longer half lives, there does not appear to be a differential dosing effect comparing subcutaneous to intravenous dosing. Therefore, in hemodialysis patients there wouldn’t be a reason to do subcutaneous injections with these agents.
ESAs and iron utilization
Normal physiology matches the serum erythropoietin concentration to iron availability to ensure efficient production of normal, iron replete erythrocytes. In contrast, injection of ESAs causes a state of iron disequilibrium. To understand this, it should be considered that of 3,500 mg of iron in the human body, only approximately 3 mg circulates at any time in the blood stream.16 Very little iron is immediately available for erythropoiesis. As opposed to normal conditions, with low basal erythropoietin concentrations and slower rates of red cell production, injection of pharmacologic doses of ESAs probably results in nonphysiologic rapid rates of red cell production. Under these conditions, the 3 mg of iron in circulation is often insufficient for optimal erythropoiesis. In theory, longer half life ESAs, or those with altered receptor interactions, could potentially result in more physiologic iron utilization. Worded differently, with slower and extended interaction between ESAs and the erythropoietin receptor, there is more opportunity to ensure sufficient iron for erythropoiesis through greater time for release of iron from storage tissues.
The clinical manifestations of iron disequilibrium induced by ESA treatment may be termed functional iron deficiency. 17 Laboratory testing shows low circulating iron and normal or increased storage iron (low transferrin saturation and normal or high serum ferritin). This pattern is commonly seen in hemodialysis patients. There has always seemed to be potential for longer half life ESAs to improve iron utilization. However, there has been little published data to support this hypothesis.
Recently, studies of peginesatide have indicated that this ESA may indeed have favorable iron utilization characteristics. A post hoc analysis of IV iron use was conducted of 1,608 hemodialysis patients who participated in a phase 3 study comparing the efficacy and safety of peginesatide to epoetin. 13 IV iron use was calculated as the median (25th-75th percentile) dose normalized over weeks 0-60 of study. Baseline serum ferritin and TSAT were similar between the groups. Requirements for IV iron were found to be significantly reduced in the peginesatide group compared to the epoetin group during study (148.8 vs. 168.5 mg/month, p=0.001). In addition, TSAT, but not serum ferritin levels were significantly increased in the peginesatide group. The results suggest that peginesatide, and by analogy perhaps other longer acting ESAs, may improve iron utilization. 18 Since this drug is not currently being marketed, the question remains open whether other longer-acting ESAs such as methoxy polyethylene glycol-epoetin beta may also share this iron sparing effect.
Conclusion
The major differentiating factor for currently marketed ESAs is serum half-life and related dosing frequency. It would appear to be advantageous to extend dosing frequency when possible. Other differentiating factors remain speculative and require further study. Newer ESAs in development may offer other advantages; lower serum erythropoietin levels, oral administration and greater iron utilization. -by Steven Fishbane, MD; Hitesh H. Shah, MD
References
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