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Darbepoetin alfa for anemia in chronic kidney disease Expert Rev. Clin. Pharmacol. 1(3), 369–379 (2008)

Anil K Agarwal N 210 Means Hall, 1654 Upham Drive, Columbus, OH 43210, USA Tel.: +1 614 293 4997 Fax: +1 614 293 3073 [email protected]

Anemia of chronic kidney disease (CKD) is common, yet it is often under-recognized and undertreated, with serious adverse consequences. It is highly responsive to treatment with erythropoiesis-stimulating agents (ESAs). Darbepoetin alfa is a hyperglycosylated ESA that has a lower affinity to the erythropoietin receptor but a longer half-life than recombinant human erythropoietin, irrespective of administration by a subcutaneous or intravenous route. Owing to its pharmacokinetic characteristics, darbepoetin alfa has been used in extended dosing intervals ranging from once every week to once every 4 weeks in CKD patients on dialysis, as well as in CKD patients not on dialysis. Darbepoetin alfa has been shown to be safe and effective in clinical trials. The safety profile of darbepoetin alfa is similar to that of recombinant human erythropoietin. While target hemoglobin levels in CKD anemia remain debatable, treatment of anemia with ESAs has the proven benefits of reducing transfusions and improving quality of life. Darbepoetin alfa has the potential to simplify the treatment of CKD anemia with many advantages, including infrequent dosing, improved patient convenience and compliance, and decreased healthcare resource utilization. KEYWORDS: anemia • chronic kidney disease • darbepoetin alfa • erythropoiesis-stimulating agent

Anemia develops early and worsens with the progression of kidney disease due to inadequate production of erythropoietin by failing kidneys. Lack of erythropoietin results in decreased stimulation of the bone marrow along with decreased production, maturation and increased apoptosis of red blood cells. Other factors, such as iron deficiency, nutritional inadequacy, inflammation, secondary hyperparathyroidism and blood loss, contribute to the pathogenesis of anemia of chronic kidney disease (CKD). Administration of erythropoiesis-stimulating agents (ESAs) is highly effective in correcting anemia of CKD. Although the evidence for improvement in kidney function and cardiovascular outcomes with treatment of CKD anemia is controversial, treatment with ESA is proven to improve quality of life and reduce the number of blood transfusions. At present, recombinant human erythropoietin alfa (epoetin) and darbepoetin alfa are the only two ESAs approved for use in the USA. Epoetin beta is commonly used in other countries. Treatment with epoetin alfa typically requires subcutaneous administration at frequent intervals, with frequent laboratory tests to monitor hemoglobin (Hb) concentration [1]. This leads to high resource utilization (due to the need www.expert-reviews.com

10.1586/17512433.1.3.369

for frequent injections and laboratory tests), poor medication compliance and lifestyle adjustment for the patient [2,3]. Frequent administration also results in ‘cycling’ of Hb levels with constant fluctuations above and below the desired range [4]. Darbepoetin alfa has the advantage of having a long half-life, which permits dosing at extended intervals and has the potential for improving treatment of anemia of CKD. Structure of darbepoetin alfa

Darbepoetin alfa is a sialoglycoprotein that differs from epoetin alfa in containing five changes in the amino acid sequence due to the presence of two extra N-linked carbohydrate chains (FIGURE 1) [5]. This allows the addition of up to a maximum of eight more sialic acid residues, which increases the molecular weight of darbepoetin alfa. The carbohydrate (CHO) content of darbepoetin alfa increases to 52%, from 40% in epoetin alfa [6]. Upon binding to the erythropoitin (EPO) receptor, darbepoetin alfa stimulates a cascade of events that leads to the proliferation and differentiation of immature red cells. It is also possible that darbepoetin alfa prolongs the half-life of red cells by decreasing apoptosis and neocytolysis.

© 2008 Expert Reviews Ltd

ISSN 1751-2433

369

Drug Profile

Agarwal

Epoetin alfa

Darbepoetin alfa Additional CHO side chains

CHO side chains

Receptor 1

Receptor 2

Receptor 1

• Three N-linked (CHO) chains • Maximum 14 sialic acids • MW ~30,400 Da • 40% CHO

Receptor 2

• Five N-linked (CHO) chains • Maximum 22 sialic acids • MW ~37,100 Da • 51% CHO

determined to be approximately 70 h in patients with CKD on dialysis [10]. The difference in half-life in this study was due to a sampling interval of 4 weeks compared with 1 week in the previous study. The longer half-life of subcutaneous darbepoetin alfa is felt to reflect slower absorption. The level of renal function does not affect the elimination half-life in CKD patients, based on preliminary data [11]. The route of elimination of darbepoetin alfa is not fully understood, although it is possible that it is endocytosed by the EPO receptor and then degraded [12]. The pharmacokinetic properties of darbepoetin alfa make dosing at extended intervals possible using either intravenous or subcutaneous routes [13,14].

Figure 1. Darbepoetin alfa differs from recombinant epoetin alfa in having two extra N-linked carbohydrate chains and a higher number of sialic acid residues. These differences increases MW, decreases receptor affinity and increases duration of action Review of clinical evidence of darbepoetin alfa. Darbepoetin alfa has been used to raise CHO: Carbohydrate; MW: Molecular weight. Hb in patients with CKD anemia not on Reproduced with permission from [5].

Pharmacokinetics & pharmacodynamics

The serum half-life and in vivo activity of currently available ESAs depend on their sialic acid and CHO content. Darbepoetin alfa, with five N-linked CHO chains (three in epoetin alfa), has a threefold longer half-life compared with epoetin alfa. Darbepoetin alfa has low affinity to the EPO receptor, allowing it to bind, dissociate and rebind with the receptor. This avoids rapid internalization and degradation of the darbepoetin alfa molecule after binding to the receptor. Slower metabolism of the compound contributes to an increase in its terminal halflife. Thus, the pharmacokinetic properties of darbepoetin alfa and epoetin alfa differ in their in vitro receptor-binding affinity, serum elimination half-lives following intravenous and subcutaneous administration, clearance and the time to reach maximum serum concentration following subcutaneous administration (Tmax) [6]. TABLE 1 shows a comparison of darbepoetin alfa with epoetin alfa [7]. The pharmacokinetics of darbepoetin alfa were examined in a double-blind, randomized, crossover study of peritoneal dialysis patients. The elimination half-life of darbepoetin alfa was found to be 25.3 h with intravenous administration and 48.8 h with subcutaneous administration (FIGURE 2A) [8]. The elimination halflife of intravenous epoetin alfa was 8.5 h. There was no difference in dose requirement between the intravenous and subcutaneous administration routes of darbepoetin alfa (FIGURE 2B). The bioavailability of darbepoetin alfa administered subcutaneously is only 37% of the darbepoetin alfa administered intravenously but darbepoetin alfa has greater biological activity than epoetin alfa in vivo [9]. More recently, based on an extended sampling schedule of 4 weeks, the terminal half-life of darbepoetin alfa was

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dialysis, as well as in those on dialysis. as shown in the studies now described. Starting with less than once-a-week administration, the dosing interval has gradually been extended to once a month with significant success in the correction and maintenance of Hb in multiple studies. Darbepoetin alfa once weekly or every other week in dialysis patients

Correction of anemia was attempted with once or three-times weekly administration of darbepoetin alfa in multicenter, sequential dose-escalation studies. Two dose levels (0.45 and 0.75 µg/kg/week) of darbepoetin alfa were administered intravenously in 75 hemodialysis (HD) patients and subcutaneously in 47 peritoneal dialysis (PD) patients [15]. In those achieving the primary end point of at least 1 g/dl increase in Hb after 4 weeks, darbepoetin alfa was continued for up to 52 weeks. Both dose levels and dosing intervals resulted in an increase in Hb by at least 1 g/dl in 60–80% of patients in both studies. For patients who continued treatment up to 52 weeks, Hb was maintained between 10 and 13 g/dl from mean baseline values of 8.4 and 8.7 g/dl. Maintenance of Hb with darbepoetin alfa at extended dosing in dialysis patients already receiving epoetin alfa has been examined in many studies. In a 28-week study, HD patients receiving epoetin alfa therapy were randomized to continue threetimes weekly intravenous administration (n = 338) or change to intravenous darbepoetin alfa administered once weekly (n = 169). A baseline weekly dose of epoetin alfa was converted to the equivalent protein mass of darbepoetin alfa (i.e., 200 units epoetin alfa = 1 µg of darbepoetin alfa). The dose was titrated to maintain Hb concentrations within -1.0 to +1.5 g/dl of patients’ baseline values and within a range of

Expert Rev. Clin. Pharmacol. 1(3), (2008)

Darbepoetin alfa for anemia in chronic kidney disease

Drug Profile

Table 1. Comparison of structure, pharmacokinetics and pharmacology of darbepoetin alfa and epoetin alfa. Characteristic

Epoetin alfa

Darbepoetin alfa

Structural

Identical to endogenous human EPO:

Differs from endogenous human EPO:

• 165 amino acids

• 165 amino acids, with five substitutions via site-directed mutagenesis

• 3 N-linked carbohydrate chains

• 5 N-linked carbohydrate chains

• ≤14 sialic acid residues

• ≤22 sialic acid residues (more negatively charged)

• ∼40% carbohydrate

• 51% carbohydrate

• MW = 30.4 kDa

• MW = 37.1 kDa

Volume of distribution similar to plasma volume

No published data are available, but assumed similar to epoetin alfa

Distribution and metabolism

Metabolism believed to occur in kidney, liver and bone marrow Receptor-binding affinity Higher affinity

Lower affinity

IC50 = 138 pM

IC50 = 703 pM

Biologic activity

Equivalent to endogenous human EPO

In rodents, 13- to 14-fold higher than endogeneous human EPO

In vitro bioactivity

EC50 = 11.5 pM

EC50 = 58.9 pM

t1/2 (iv.)

∼8.5 h

∼25.3 h

t1/2 (sc.)

∼16–19 h

∼33–48 h

Bioavailability

20–30%

37%

CL/F

24.7 ml/h/kg

3.7 ml/h/kg

Tmax

16 ± 7.5 h (sc. in volunteers)

86.1 ± 22.8 h (sc. in cancer patients)

Tmax

18 h (sc. in dialysis patients)

54.1 ± 5.1 h (sc. in dialysis patients)

Pharmacokinetics

CL/F: Relative clearance after sc. administration; EC: Effective concentration; EPO: Erythropoietin; IC: Inhibitory concentration; iv.: Intravenous; MW: Molecular weight; pM: Picomolar; sc.: Subcutaneous; t1/2 : Elimination half-life; Tmax: Time to reach peak serum concentration. Data reproduced with permission from [7].

9.0–13.0 g/dl [16]. Hb was maintained in both groups, establishing the efficacy of weekly darbepoetin alfa in dialysis patients. Weekly doses at baseline and during the evaluation period were 12,706 and 13,639 units for epoetin alfa and 63.18 and 54.18 µg for darbepoetin alfa, respectively. Thus, the change in dose during the two periods was insignificant. In a randomized, open-label, 52-week trial of 522 patients on HD and PD, those receiving subcutaneous or intravenous epoetin alfa were randomized in a 1:2 ratio to continue epoetin alfa (n = 175) or darbepoetin alfa at extended doses, either once weekly or once every other week if the original epoetin alfa dose was once weekly (n = 66), twice weekly (n = 118) or three-times weekly (n = 163), respectively [9]. Dose conversion was again 200 IU epoetin alfa = 1 µg darbepoetin alfa, based on the peptide mass conversion factor. The dose of both agents was titrated to maintain Hb close to the patient’s baseline level. The primary end point results showed similar mean change in Hb

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between baseline and the evaluation period at weeks 25–32 of treatment with both agents. Over 95% of the patients maintained their Hb irrespective of the ESA schedule. Dosing during the evaluation period was similar to baseline and was also similar among treatment groups. The mean treatment difference, when the dosing units of epoetin alfa were converted to the dosing units of darbepoetin alfa, was -0.40 µg/week (95% confidence interval: -5.9–5.2). The epoetin alfa dose requirements were 22% lower by the subcutaneous route compared with the intravenous route, although this difference was not significant for darbepoetin alfa. In a similar 24-week study, dialysis patients (n = 341) stable on epoetin (alfa or beta) were switched to darbepoetin alfa at a reduced dosing frequency by the same route of administration and schedule as in the previous study [17]. The darbepoetin alfa dose was titrated to maintain Hb concentrations within -1.0 and +1.5 g/dl of the individual mean baseline Hb and between 10 and 13 g/dl. During the evaluation period

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Drug Profile

Agarwal

A

Baseline-corrected serum concentration (ng/ml)

10

Darbepoetin alfa Epoetin alfa

1

Darbepoetin alfa once a month in dialysis patients 0.1

0.01 0

12

24 48 50 72 36 Time postinjection (h)

84

96

Baseline-corrected darbepoetin alfa serum concentration (ng/ml)

B 10

sc. administration iv. administration

1

0.1

0.01 0

24

48 72 96 120 Time postinjection (h)

144

168

Figure 2. Pharmacokinetic profiles of darbepoetin alfa and epoetin alfa administration. (A) Darbepoetin alfa and epoetin alfa administered via the iv. route. (B) Pharmacokinetic profile of darbepoetin alfa administered iv. and sc. iv.: Intravenous; sc.: Subcutaneous. Reproduced with permission from [8].

(weeks 21–24), Hb levels were maintained. Mean Hb concentrations increased by 0.58 g/dl in patients receiving intravenous darbepoetin alfa but remained unchanged in patients receiving subcutaneous darbepoetin alfa. Mean weekly intravenous darbepoetin alfa doses decreased (p = 0.004) and subcutaneous doses increased slightly during the study period (p = 0.014). Another multicenter, prospective, open-label, 24-week study enrolled 1502 dialysis subjects on stable epoetin alfa treatment and switched them to darbepoetin alfa at extended dose intervals by the same route of administration (900 intravenous and 602 subcutaneous) as that of previous epoetin alfa [18]. Subjects receiving epoetin alfa two- (27%) or three-times (59%) weekly were switched to darbepoetin alfa once weekly, and those receiving epoetin alfa once weekly (14%) were switched to darbepoetin alfa once every 2 weeks; the darbepoetin alfa dose was titrated to maintain Hb concentrations of 10–13 g/dl. Hb was

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maintained regardless of darbepoetin alfa dosing schedule, with a mean change in Hb from baseline to the evaluation period (weeks 21–24). The mean Hb concentration increased by 0.19 g/dl in subjects receiving intravenous darbepoetin alfa and was unchanged in patients treated with subcutaneous darbepoetin alfa. Subjects with baseline Hb of less than 11 g/dl experienced a clinically relevant increase in mean Hb concentration of 0.67 g/dl from baseline to the evaluation period.

Treatment with once-monthly darbepoetin alfa was also attempted [19,20]. The study by Jadoul et al. [20] was an extension of the previous study by Vanrenterghem. Dialysis patients with stable Hb concentration (10.0–13.0 g/dl) on stable darbepoetin alfa therapy once every 2 weeks were converted to darbepoetin alfa once every 3 weeks for 20 weeks, and if Hb remained stable, they were continued on darbepoetin alfa once every 4 weeks for 20 weeks. Darbepoetin alfa dose was titrated to maintain Hb levels within a target range (-1.0 to +1.5 g/dl of baseline Hb and between 10.0 and 13.0 g/dl). Success with the extended dosing interval was defined as maintenance of a mean Hb of at least 10.0 g/dl during a 4-week evaluation at the end of the dosing period. In total, 54 patients (39% of the previous cohort of 522 patients) received darbepoetin alfa once every 3 weeks and, of these, 38 patients were converted to darbepoetin alfa once every 4 weeks. Of these, 36 patients were considered evaluable; 30 (83%) of those successfully maintained target Hb. There was no significant change in median weekly dose at once every 3 weeks or once every 4 weeks administration from a baseline median weekly dose of darbepoetin alfa. The study was not randomized and patients were selected for once every 4 weeks administration of darbepoetin alfa based on their success of maintaining Hb with every 3 weeks administration. Darbepoetin alfa once weekly or every other week in patients with CKD not on dialysis

The treatment of anemia in patients with CKD not on dialysis involves a subgroup of patients with different dynamics and requires a different approach to management than dialysis patients. Correction and maintenance of Hb levels with onceweekly darbepoetin alfa was tested in a multicenter, randomized, open-label study of 166 epoetin alfa-naive patients with chronic renal insufficiency. They were randomized in a 3:1 ratio to receive darbepoetin alfa (0.45 µg/kg once weekly) or epoetin alfa (50 U/kg twice weekly), administered subcutaneously for up to 24 weeks [21]. Dose adjustments were made to achieve a Hb response of at least 1.0 g/dl from baseline and concentration of at least 11.0 g/dl. During the 24-week treatment period, 93% of patients receiving darbepoetin alfa and 92% of patients receiving epoetin alfa achieved a Hb response. The median time to response was 7 weeks in both groups. After correction, mean Hb concentrations were maintained within the target range of 11.0–13.0 g/dl for the remainder of the 24-week treatment period. No dose adjustment was needed in 58% of darbepoetin

Expert Rev. Clin. Pharmacol. 1(3), (2008)

Darbepoetin alfa for anemia in chronic kidney disease

alfa patients and 59% of epoetin alfa patients. Median doses of darbepoetin alfa and epoetin alfa at the time of response were 0.46 µg/kg and 100 U/kg, respectively, decreasing to 034 µg/kg and 56.9 U/kg at 24 weeks. Darbepoetin alfa was administered once every other week to correct and maintain Hb levels in patients with CKD naive to ESA [22]. In this multicenter, open-label study, 76 epoetin alfanaive patients were enrolled to receive darbepoetin alfa (0.75 µg/kg) once every other week for up to 24 weeks. Doses were titrated to achieve and maintain a Hb target of 11.0–13.0 g/dl. Of patients completing 24 weeks of treatment, 97% achieved a Hb response. The median time to response was 5 weeks; the median darbepoetin alfa dose was 60 µg and darbepoetin alfa was safe and well tolerated. No antibodies to darbepoetin alfa were detected. In another large study (n = 608) of ESA-naive CKD patients with Hb levels of less than 11.0 g/dl, darbepoetin alfa was administered at an initial dosage of 0.75 µg/kg once every other week and the dose titrated to achieve and maintain Hb levels of 11–13 g/dl for up to 24 weeks [23]. Of 463 participants who completed the study, 95% achieved a Hb response. The mean darbepoetin alfa dose was 63.5 µg and the mean time to Hb response was 5.7 weeks. Oral iron therapy was administered to 60% and intravenous iron to 16% of the participants. In a 52-week study, patients on every-other-week darbepoetin alfa were also able to maintain Hb [24]. Darbepoetin alfa once a month in patients with CKD not on dialysis

To assess the feasibility of extending the dosing interval beyond 2 weeks, a multicenter, open-label study of patients with CKD not on dialysis enrolled 97 patients receiving stable subcutaneous darbepoetin alfa every 2 weeks and converted them to darbepoetin alfa once monthly for 29 weeks [25]. Hb concentration was maintained within the target range (10–12 g/dl) in 79% of all patients by intention-to-treat analysis and in 85% of patients who completed the study. The mean ± standard deviation monthly darbepoetin alfa dose was similar between baseline (88.7 ± 49.9 mg) and the evaluation period (86.6 ± 78.8 mg). The safety profile was similar to the previous regimen. In a similar, open-label, multicenter, 33-week study of 152 CKD patients, the goal Hb range was 11–13 g/dl [26]. During evaluation, 76% of patients by intention to treat and 85% of those completing the study achieved this goal. The dose of darbepoetin alfa was 124 µg and there were no unusual safety concerns. Once-monthly darbepoetin alfa was also used in 68 CKD stage 3–5 patients, who were either naive or were receiving epoetin alfa treatment, and a computerized anemia management program (CAMP) was utilized to maintain a target Hb of 11–13 g/dl [27]. The study was different in that the dose of darbepoetin alfa was based on current Hb level rather than bodyweight. Over 60% of patients achieved goal Hb over 300 days of treatment.

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Drug Profile

Studies of special populations: elderly & long-term care patients

Anemia is common in elderly and in long-term care facility residents; it is also associated with a higher hospitalization rate, risk of falls, poor quality of life and lower survival [28– 31]. De novo every-other-week treatment with darbepoetin alfa in older CKD subjects over a 19-week period was shown to achieve Hb of at least 11 g/dl in 94% of those younger than 65 years (baseline 9.9; final 12.2), 94% of those 65 years or older (baseline 10.0; final 12.6) and 86% of those over 75 years (baseline 10.0; final 12.2) of age [32]. Darbepoetin alfa was administered once monthly in older adults stable at every 2-week darbepoetin alfa administration [33]. In total, 79% of the subjects aged 65 years or older and 80% of subjects aged 75 years or older maintained their Hb levels within the specified target range, compared with 80% of subjects younger than 65 years of age. Hb levels and darbepoetin alfa doses did not change significantly from baseline to the evaluation period. Darbepoetin alfa administered once a month was well tolerated in all age groups. In a similar study, there was 90% response in those aged over 65 and over 75 years [34]. Thus, darbepoetin alfa is at least equally effective in older adults. In fact, there was a slight decline in darbepoetin alfa dose in the elderly, the reason for which is not clear, although it could be related to a lower bodyweight in this age group. Safety: tolerability & adverse reactions

Darbepoetin alfa is generally well tolerated and the side effects most commonly seen in clinical trials are similar to those seen with epoetin alfa and occur in more than 20% of the patients receiving either agent. Many side effects can also be attributed to the underlying kidney disease and comorbidities, and are common to treatment with both darbepoetin alfa and epoetin alfa. The most common adverse effects include infection, hypertension, hypotension, myalgia, headache and diarrhea. A higher rate of nausea, vomiting and thrombosis of vascular access has been shown in the darbepoetin alfa arm of some trials. Exacerbation of hypertension and increased number of vascular thrombotic events occur with darbepoetin alfa, similar to epoetin alfa. Vascular access thrombosis in HD patients receiving darbepoetin alfa occurred in clinical trials at an annualized rate of 0.22 events per patient year. Rates of thrombotic events (e.g., vascular access thrombosis, venous thrombosis and pulmonary emboli) with darbepoetin alfa were similar to those observed with other recombinant erythropoietins [35]. When hematocrit was maintained at 35 ± 3% in clinical trials, clotting of the vascular access in those receiving epoetin alfa occurred at an annualized rate of approximately 0.25 events per patient year, and other thrombotic events (e.g., myocardial infarction, cerebral vascular accident, transient ischemic attack and pulmonary embolism) occurred at a rate of 0.04 events per patient-year. In a separate study of 1111 untreated dialysis patients, clotting of the vascular access occurred at a rate of 0.50 events per patient-year. In HD

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Drug Profile

Agarwal

patients with clinically evident ischemic heart disease or congestive heart failure, the risk of A–V shunt thrombosis was higher (39 vs 29%; p < 0.001), and myocardial infarctions, vascular ischemic events and venous thrombosis were increased in patients targeted to hematocrit of 42 ± 3% compared with those maintained at 30 ± 3% [1]. Treatment with ESAs has been associated with an increase in the risk of cardiovascular events and death with a high Hb target and rapid increase in Hb, which should be avoided. The adverse events, rates of withdrawal and death have been similar in clinical trials of the two agents. Uncontrolled hypertension and hypersensitivity to darbepoetin alfa are contraindications to its use. The occurrence of pure red cell aplasia (PRCA) is an uncommon event but has been reported with darbepoetin alfa [36–38]. With epoetin alfa, the reported frequency is approximately 0.2/100,000 patient-years (excluding a specific European formulation known as Eprex®) and occurs due to the spontaneous development of neutralizing antibodies to erythropoietin. PRCA is manifested by severe anemia, low reticulocyte count, absence of free erythropoietin in blood and presence of neutralizing antibodies. Antibodies to EPO causing PRCA can be detected using a variety of laboratory tests that include radioimmunoprecipitation (RIP) assay, ELISA, surface plasmon resonance (SPR) and bioassays that measure neutralizing antibodies [39]. If antibodies to darbepoetin alfa are detected, therapy with any currently available ESA, including darbepoetin alfa, should be discontinued. PRCA may respond to immunosuppressive therapy. Pharmacoeconomics

The treatment of anemia in CKD is an expensive proposition. Prior to the availability of ESA, the treatment involved frequent blood transfusions with their attendant cost and side effects. Left untreated, anemia is not inexpensive, with consequences including suboptimal quality of life, need for blood transfusions, increased incidence of left ventricular hypertrophy, congestive heart failure and death [40,41]. Both darbepoetin alfa and epoetin alfa are highly effective in correcting and maintaining Hb in patients with CKD with or without dialysis and have a similar safety and tolerability profile. There are no head-to-head trials comparing the cost–effectiveness of the two drugs. Thus, the comparison between the two can only be accomplished by estimating the cost of treatment. This issue has been discussed in detail elsewhere [7]. Based upon the average wholesale price in 2003, there was a higher cost of equivalent dose of darbepoetin alfa compared with epoetin alfa, as shown in TABLE 2 [7]. However, the analysis did not discuss the impact of more realistic acquisition costs or the costs of resources utilized in frequent administration of ESA, such as the amount of time for travel to the physician’s office, number of injections and related supplies, and cost of monitoring related to frequency of injections. In a time and motion study, the requirement of practice resources, excluding the cost of the drug, was compared for once-weekly or once-monthly administration of ESA in nondialysis CKD

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patients [42]. All activities, including those related to patient visit, dose administration, front office, billing and drug inventory were recorded. The study estimated that once-monthly dosing would require, on average, 83 h less staff time and US$2044 less estimated cost treating 200 patients per month compared with weekly administration per clinic. While the patient-related costs (travel time, frequent injections and family time) are not counted, the study attempts to focus on a global cost of treatment of CKD anemia with extended dosing, rather than just the cost of ESAs. Expert commentary: current view & strategy in treatment of anemia

Multiple observational studies over the last few decades have shown that anemia is a risk factor for cardiovascular events [40,44]. Anemia of CKD leads to poor quality of life and an increased number of blood transfusions. It is also associated with higher rates of hospitalization and mortality in patients with CKD, anemia has been called a mortality multiplier in CKD [45,46]. There is also observational evidence for faster progression of CKD in those with anemia. The advent of ESA therapy has revolutionized the management of CKD anemia and improved the life of patients with CKD. Despite the availability of traditional therapy with frequently administered epoetin alfa, anemia in CKD is underrecognized and undertreated; almost half of patients initiating dialysis presented with Hb less than 10 g/dl and two-thirds had Hb less than 11 g/dl in 2006 [47]. Although the treatment of anemia in CKD has come of age, the understanding of risks and benefits of treating anemia has become more and more complex – even controversial – with time. In small, randomized trials, partial correction of anemia was shown to improve quality of life, reduce the number of blood transfusions, decrease hospitalizations and slow the rate of progression of kidney disease [48–50]. In large, randomized, controlled trials of higher Hb targets, there is no evidence for improvement in cardiovascular outcomes. Although normalization of Hb makes physiological sense, comorbidities and complications of CKD may compromise the vascular system so that it may not tolerate normal Hb or red cell mass. Full correction of anemia was indeed associated with higher risk of cardiovascular events [51–53]. The quality-of-life benefits have been substantiated by most, but not all studies. Kidney disease progression was either not affected or worsened. Following the publication of the Correction of Haemoglobin and Outcomes in Renal Insufficiency (CHOIR) [52] and Cardiovascular Risk Reduction by Early Anaemia Treatment with Epoetin Beta (CREATE) [53] studies in 2006, the US FDA issued a black-box warning to limit the use of ESAs to increase Hb to the lowest level necessary to avoid blood transfusions. A meta-analysis of randomized, controlled trials has also shown evidence of detrimental effects of higher Hb targets [54]. Data from randomized, controlled trials, such as Trial to Reduce End points with Anemia Treatment (TREAT) will help to clarify the benefits and risks of anemia treatment with extended dosing of darbepoetin alfa [55].

Expert Rev. Clin. Pharmacol. 1(3), (2008)

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Open-label, randomized comparison of DA with Epo in patients with CKD 3:1 DA (n = 129) Epo (n = 37) 24 weeks duration

Study design (Patients treated; n)

Efficacy end points

DA: initial q.w. iv. dose based on prior weekly Epo (200 U:1 µg); titrations based on two consecutive weekly [Hb]. Epo: stable iv. t.i.w. dose continued

CKD on dialysis; baseline Hb between 9 and 12.5 g/dl

Primary: Mean change in [Hb] equivalent to Epo Secondary: Percent of patients with [Hb] in target and therapeutic range % Unstable [Hb] requiring adjustment Within patient variance in [Hb]; dose of study drug

Primary: [Hb] comparable Secondary: All [Hb] variables comparable Mean doses during evaluation period (weeks 21–28) were similar to baseline: DA: 54.2 µg/q.w. Epo: 12,639 U/q.w.

Primary: DA: 93% responders Epo: 92% responders Secondary: Comparable efficacy (see text for details) Median weekly maintenance dose at end of study (week 24): DA: 0.34 µg/kg Epo: 56.9 U/kg

Results

DA: US$15,561/year using 60 µg vials iv. q.w. Epo: US$10,418/year using 20000 U/2 ml multidose vial for t.i.w. dosing (three doses/vial)

Cost per 24 weeks assuming no dosage adjustments: DA: US$4778 Epo: US$2564 Annual cost based on median dose at end of study: DA: US$6484/year Epo: US$2778/year First year cost adjusted for nonresponse and maintenance: DA: US$7318/1st year Epo: US$3487/1st year

Calculated average costs of therapy*



If based on weight, calculted for a 70-kg adult for the study period indicated; range of costs described in text. Randomizations discovered to be reversed upon study unblinding; study was originally intended to treat 2:1 DA:Epo. AE: Adverse event; b.i.w.: Twice weekly; CKD: Chronic kidney disease; DA: Darbepoetin alfa; Epo: Epoetin alfa; Hb: Hemoglobin; [Hb]: Hemoglobin concentration; HD: Hemodialysis; iv.: Intravenously; n: Number of patients evaluated in each study arm; PD: Peritoneal dialysis; sc.: Subcutaneously; t.i.w.: Three-times weekly; q.o.w.: Every other week; q.w.: Every week; U: Units. Reproduced with permission from [7].

*

Nissenson et al. Blinded, randomized comparison of DA with Epo in dialysis patients 1:2 DA (n = 169) Epo (n = 335)‡ 28 weeks duration

Entry criteria

DA: 0.45 µg/kg CKD: Primary: q.w. sc. Hb < 11 g/dl Proportion with Hb response: Epo: 50 U/kg b.i.w. ≥ 1 g/dl from baseline; sc.; adjust by 25% to [Hb] ≥ 11 g/dl during 24-week maintain Hb between period 11 and 13 g/dl Secondary: Time to achieve response ↑ [Hb] over time; Dose at time of Hb response and at week 24 Number of transfusions

Dosing regimens

Hemodialysis (chronic kidney disease)

Locatelli et al.

Predialysis

Study

Table 2. Clinical studies and cost analysis for epoetin alfa and darbepoetin alfa in patients with chronic kidney disease.

[16]

[17]

Ref.

Darbepoetin alfa for anemia in chronic kidney disease

Drug Profile

375

376

Study design (Patients treated; n)

Dosing regimens

DA: initial dose based on prior weekly Epo dose (200 U:1 µg) t.i.w. Epo switched to q.w. DA; q.w Epo switched to q.o.w. DA; iv. or sc. route maintained Epo: continue stable iv. or sc. t.i.w. or q.w. dose

Vanrenterghem Open-label, et al. randomized comparison of DA with Epo 2:1 DA (n = 334) Epo (n = 175) 52 weeks duration

CKD on dialysis; Baseline Hb between 9 and 12.5 g/dl

CKD on dialysis; Baseline Hb ≤ 10 g/dl

Entry criteria

Primary: Mean change in [Hb] Equivalence to Epo analyzed in subgroups q.w., q.o.w., iv., sc. and dialysis modality PD or HD Secondary: Percentage with [Hb] in target and therapeutic range Percentage with [Hb] requiring adjustment within pt variance in [Hb] dose of study drug

Primary and secondary not specified Study measured: Percentage of patients to achieve target [Hb] ≥ 11 g/dl Mean ↑ [Hb] over 4 weeks Time to achieve target Median maintenance dose Safety

Efficacy end points

Primary: [Hb] comparable Secondary: all [Hb] variables comparable iv. doses of DA similar to sc. iv. doses of Epo higher than sc doses Average DA sc ~28 µg/week Average DA iv. ~27 µg/week Average Epo sc ~5000 U/week Average Epo iv. ~6700 U/week

DA: 72% responders Mean ↑ [Hb] over 4 weeks = 1.1 g/dl Median time to Hb response = 10 weeks Median dose = 0.56 µg/kg/q.w. 98% had AEs Epo: 84% responders Mean ↑ [Hb] over 4 weeks = 1.33 g/dl Median time to Hb response = 8 weeks Median dose = 156 U/kg/q.w. 100% had AEs

Results

DA: sc. or iv. US$10,374/year with considerable wastage from 40 µg vials; if dose is rounded down to use 25 µg vials, costs are lowered to US$6483/year Epo: sc. US$3473/year; iv. US$4630/year using 20,000 U/2 ml multidose vial

DA: US$10,374/year using 40 µg vials Epo: US$8334/year using 20,000 multidose vials (five doses/vial)

Calculated average costs of therapy*



If based on weight, calculted for a 70-kg adult for the study period indicated; range of costs described in text. Randomizations discovered to be reversed upon study unblinding; study was originally intended to treat 2:1 DA:Epo. AE: Adverse event; b.i.w.: Twice weekly; CKD: Chronic kidney disease; DA: Darbepoetin alfa; Epo: Epoetin alfa; Hb: Hemoglobin; [Hb]: Hemoglobin concentration; HD: Hemodialysis; iv.: Intravenously; n: Number of patients evaluated in each study arm; PD: Peritoneal dialysis; sc.: Subcutaneously; t.i.w.: Three-times weekly; q.o.w.: Every other week; q.w.: Every week; U: Units. Reproduced with permission from [7].

*

DA: 0.45 µg/kg/q.w. Epo: 150 U/kg divided t.i.w.

Randomized comparison of DA with Epo in dialysis patients 3:1 DA (n = 90) Epo (n = 31) 20 weeks duration

Coyne et al.

Hemodialysis (chronic kidney disease) (cont.).

Study

Table 2. Clinical studies and cost analysis for epoetin alfa and darbepoetin alfa in patients with chronic kidney disease (cont.).

[13]

Ref.

Drug Profile Agarwal

Expert Rev. Clin. Pharmacol. 1(3), (2008)

Darbepoetin alfa for anemia in chronic kidney disease

Based on the current evidence, it is prudent to continue to target Hb levels to a range of 10–12 g/dl and avoid going above 12 g/dl level. The National Kidney Foundation Kidney Disease Outcome Quality Initiative (K/DOQI) now recommends target Hb levels of 11–12 g/dl [43]. Guidelines provide a step-by-step approach to the management of anemia, starting with estimation of glomerular filtration rate for timely diagnosis of CKD along with measurement of Hb and basic investigation of anemia. Once the obvious causes of anemia are ruled out, ESA therapy is recommended. The guidelines, although imperfect due to a lack of evidence for most of the recommendations, have helped to improve the treatment of CKD anemia. The availability of agents that allow extended dosing has the potential to simplify treatment and monitoring of CKD anemia. Other products on the market for CKD anemia

Since the advent of darbepoetin alfa, a number of other ESAs with long half-lives are in clinical development, although they are yet to be approved for clinical use universally. These include erythropoietin analogues (continuous erythropoietin receptor activator [CERA] – a pegylated erythropoietin-β), erythropoietin mimetics (Hematide™ – a pegylated peptide) and hypoxiainducible factor 1-alfa activators (FG 2216 and FG 4592). CERA has recently been approved for use in the EU. Many other compounds are in the advanced stages of clinical trials. Hematide has the distinction of bearing no similarity to erythropoietin molecules and being able to stimulate the EPO receptor. It is unlikely to react with antierythropoietin antibodies. Hypoxiainducible factor stabilizers have a different mechanism of action and have the advantage of being administered orally. Impact on current management

Darbepoetin alfa is a significant advance in the treatment of CKD anemia. Owing to its longer half-life, it has the ability to be dosed infrequently for correction as well as maintenance of

Drug Profile

Hb levels. It provides flexibility in dosing and route of administration due to no significant difference in the dose by either route [18]. Its use will also impact healthcare resource utilization and patient convenience. Availability in prefilled syringes makes it easy for the patient to self-inject an accurate dose. The availability of a simpler treatment of CKD anemia is likely to improve the level of care of such patients. Five-year view

Treatment of CKD anemia is in constant flux. Production of synthetic epoetin alfa was one of the greatest advances in the management of CKD patients with anemia. However, optimal targets of Hb levels continue to elude us at present. It is also unclear if some of the risks and adverse events seen in those treated with ESA represent the complications inherent to the milieu of renal disease, administration of adjuvants such as iron that are used in the treatment of anemia or administration of ESA. Future research is likely to provide answers to some of these questions. The marketplace is also bringing new choices of therapeutic agents, which are likely to benefit patients and providers by improving therapeutic profile of the agents and increasing competition. The ability to dose ESA at extended dosing intervals, made possible by agents with longer half-lives, is likely to become the standard of care in the future. Financial & competing interests disclosure

A Agarwal has served as a consultant and received honoraria or lecture fees from Amgen Pharmaceuticals. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.

Key issues • Currently, only two erythropoiesis-stimulating agents (ESAs) are approved in the USA for the treatment of anemia in chronic kidney disease (CKD): recombinant human erythropoietin and darbepoetin alfa. Continuous erythropoietin receptor activator has recently been approved in Europe. • Darbepoetin alfa has molecular and pharmacokinetic characteristics that prolong its half-life, permitting less frequent administration to correct (with up to every 2 week dosing) and maintain (with up to 1–4 week dosing intervals) hemoglobin (Hb) levels. • Studies of extended dosing with darbepoetin alfa have shown evidence of efficacy and safety at variable dosing intervals in patients with CKD with or without dialysis. • Extended dosing with darbepoetin alfa can improve the management of CKD anemia by decreasing practice resource utilization and improving compliance and convenience for the patient. • Hb targets and cardiorenal risks and benefits with ESA therapy in CKD are controversial at present. There is no evidence of benefit of higher Hb targets; in fact, there is evidence of harm. • Iron supplementation, either oral or intravenous, is essential in those requiring any ESA therapy for treatment of anemia. Intravenous iron is typically administered to patients on hemodialysis. The superiority of oral or intravenous iron in those with CKD not on dialysis has not been shown in randomized, controlled studies.

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Gross AW, Lodish HF. Cellular trafficking and degradation of erythropoietin and novel erythropoiesis stimulating protein (NESP). J. Biol. Chem. 281, 2024–2032 (2006).

13

Vanrenterghem Y, Barany P, Mann JFE et al. Randomized trial of darbepoetin alfa for treatment of renal anaemia at a reduced dosing frequency compared with rHuEpo in dialysis patients. Kidney Int. 62, 2167–2175 (2002).

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Affiliation •

Anil K Agarwal Associate Professor of Clinical Medicine, The Ohio State University, N 210 Means Hall, 1654 Upham Drive, Columbus, OH 43210, USA Tel.: +1 614 293 4997 Fax: +1 614 293 3073 anil.agarwal @osumc.edu

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Darbepoetin alfa for anemia in chronic kidney disease.

Anemia of chronic kidney disease (CKD) is common, yet it is often under-recognized and undertreated, with serious adverse consequences. It is highly r...
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