1 Department of Renal Medicine, King's College Hospital, London and 2 Amgen Limited, Cambridge, UK
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Abstract |
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Methods. Two multicentre, sequential dose-escalation studies examined the i.v. route of administration of darbepoetin alfa in haemodialysis patients (n=75) and the s.c. route in peritoneal dialysis patients (n=47). Patients were randomized to receive darbepoetin alfa at doses ranging from 0.075 to 0.75 µg/kg/week administered as either a once weekly or a three-times weekly injection. Patients achieving the primary endpoint of a 1 g/dl increase in haemoglobin after 4 weeks continued darbepoetin alfa for up to 52 weeks. Safety was assessed by adverse event reports, changes in laboratory values and vital signs, and antibody screening.
Results. Darbepoetin alfa produced dose-related increases in haemoglobin over the first 4 weeks of treatment in both studies. Two dose levels (0.45 and 0.75 µg/kg/week) increased the haemoglobin by 1 g/dl in 6080% of patients, and no difference between once weekly and three-times weekly dosing was apparent. For patients who continued treatment up to 52 weeks, haemoglobin was maintained between 10 and 13 g/dl from mean baseline values of 8.4 and 8.7 g/dl. The adverse event profile was similar to that associated with rHuEpo therapy, and no antibodies to darbepoetin alfa were detected.
Conclusions. Darbepoetin alfa is safe and effective for the treatment of anaemia in dialysis patients. The optimal weekly starting dose is 0.450.75 µg/kg and once weekly dosing is possible for both the s.c. and i.v. routes of administration.
Keywords: anaemia; chronic kidney disease; darbepoetin alfa; dialysis; novel erythropoiesis stimulating protein
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Introduction |
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Although rHuEpo has proven highly effective in treating renal anaemia, administration two or three-times weekly is recommended for most patients because of its short circulating half-life [46]. Unless a patient receives a kidney transplant, treatment must continue indefinitely. The chronic nature of the disease and its treatment means that multiple weekly injections of rHuEpo may be inconvenient for both patients and healthcare providers.
Research has indicated that the sialic acid-containing carbohydrate of erythropoietin determines its serum half-life [7]. Darbepoetin alfa is a glycoprotein that was designed by introducing two extra consensus N-linked glycosylation sites. Consequently, darbepoetin alfa has five N-linked carbohydrate chains, compared with rHuEpo, which has only three. The increased carbohydrate content of darbepoetin alfa results in a terminal half-life in humans that is 3-fold longer than that of rHuEpo [8]. This novel pharmacokinetic profile offered the opportunity for reduced dosing frequency compared with rHuEpo.
Two multicentre, sequential dose-escalation studies were conducted to examine the efficacy of darbepoetin alfa for treating anaemia in patients with chronic kidney disease who were receiving haemodialysis or peritoneal dialysis.
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Subjects and methods |
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Patients aged 1875 years with chronic kidney disease and receiving haemodialysis or peritoneal dialysis for at least 2 months before the first planned dose of study drug were enrolled. Other entry criteria included a haemoglobin concentration <10 g/dl on two consecutive occasions (at least 24 h apart) and no rHuEpo therapy within 3 months before the first planned dose of study drug. Exclusion criteria included uncontrolled hypertension (diastolic blood pressure >100 mmHg), congestive heart failure (New York Heart Association Class III or IV), haematological disorders that could exacerbate anaemia, systemic infection or inflammatory disease, severe secondary hyperparathyroidism, or any other disorders that could interfere with the response to darbepoetin alfa. Red blood cell transfusions to treat anaemia and androgen therapy were prohibited within 1 and 3 months of the study start, respectively.
Study drug
Darbepoetin alfa (AranespTM, Amgen Inc., Thousand Oaks, CA) was supplied as a clear, colourless, sterile protein solution in vials containing 5, 20 and 100 µg/ml.
Study design
These two multicentre, randomized, sequential, dose-escalation studies had similar designs: both studies investigated the optimal dose and frequency of administration of darbepoetin alfa for the treatment of renal anaemia, in addition to the safety profile of the product. One study investigated intravenously administered darbepoetin alfa in patients receiving haemodialysis, and the other investigated subcutaneously administered darbepoetin alfa in patients receiving peritoneal dialysis.
All patients completed a screening period within 23 weeks before the first dose of study drug. Ten eligible patients were then to be randomized to receive the starting dose of darbepoetin alfa (0.075 µg/kg/week) administered either once weekly (n=5) or three times weekly (n=5). Subsequent dose cohorts were to be enrolled at dose levels of 0.225, 0.45, 0.75, 1.5 and 4.5 µg/kg/week until the optimal haemoglobin rate of rise was established. A Safety Monitoring Committee, comprising of study group members, reviewed data after each cohort had completed 4 weeks of study drug administration, and made the decision whether or not to escalate to the next dose level. Patients who achieved 1 g/dl increase in haemoglobin concentration after 4 weeks continued darbepoetin alfa treatment for up to 52 weeks. Those patients who did not achieve this increase were withdrawn from the study and, after a 30-day period, could be re-enrolled at a higher dose level. After the dose escalation was completed, additional patients were enrolled at effective dose levels to extend the experience with the study drug. Patients who experienced an excessive increase in haemoglobin concentration (i.e. >3 g/dl over any 4-week period) or a haemoglobin concentration >13 g/dl had their dose of darbepoetin alfa reduced to the next lowest level. If a patient's haemoglobin concentration increased to >14 g/dl, the dose of darbepoetin alfa was withheld until the haemoglobin concentration decreased to <12 g/dl, and dosing was then restarted at the next lowest dose level. After week 16, if the patient's haemoglobin concentration was <10 g/dl, the dose could be increased by 25% increments to maintain haemoglobin values within the range of 1013 g/dl.
To ensure an adequate supply of iron to support the erythropoietic response to darbepoetin alfa, patients with a screening serum ferritin level <200 µg/l received 200 mg of i.v. iron 2 weeks before the first dose of darbepoetin alfa. If the serum ferritin was <200 µg/l at any time during the study, 200 mg iron was administered intravenously every 2 weeks until the serum ferritin was >200 µg/l. Patients could also receive oral iron therapy throughout the study period.
Study endpoints
The primary endpoints of both studies were: the haemoglobin rate of rise over the initial 4 weeks of treatment; the haemoglobin value at 16 weeks of treatment; and the safety profile of darbepoetin alfa in this patient population.
Safety was assessed by summarizing reports of adverse events. All adverse events were grouped according to body systems affected and by the preferred term within the body system, according to a modified World Health Organisation adverse reaction term (WHOART) dictionary. The secondary safety endpoints were changes in vital signs and laboratory measurements (including haematocrit, red blood cell count and reticulocyte count), changes in dose, serum darbepoetin alfa levels and antibody formation to darbepoetin alfa.
Statistical analysis
All patients who received at least one dose of study drug were included in the analyses of efficacy and safety. Patients were analysed according to the dose level and schedule assigned at randomization, irrespective of the dose and schedule they actually received. Patients who re-entered the study after withdrawal due to an insufficient increase in haemoglobin concentration were included in the efficacy analysis set at each of the dose-by-schedule combinations to which they were randomized.
The presence of a dose-by-schedule interaction was investigated with analysis of variance using an =0.1 (10%) level of significance for the primary endpoint (i.e. haemoglobin rate of rise over the initial 4 weeks of therapy). All other significance tests used the
=0.05 (5%) level of significance. All tests were carried out against a two-sided alternative hypothesis. No adjustment was made for multiple comparisons. For all statistical comparisons, the treatment difference was estimated and an associated 95% confidence limit calculated.
Descriptive statistics were summarized for all endpoints by treatment group. For safety endpoints, summary statistics were tabulated by dose-by-schedule combination. If appropriate, data were pooled across dose schedule, and summary statistics were generated.
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Results |
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Efficacy evaluation
Haemoglobin rate of rise over initial 4 weeks. The results of both studies indicate a dose-related increase in haemoglobin concentration over the first 4 weeks of darbepoetin alfa treatment (Figure 1). This increase was statistically significant in both studies (P=0.029 for patients receiving i.v. darbepoetin alfa; P=0.003 for patients receiving s.c. darbepoetin alfa). No difference was apparent between the haemoglobin response for the two dose schedules (once weekly and three-times weekly). The proportion of patients achieving a haemoglobin response over the first 4 weeks was 6080% with darbepoetin alfa administered at doses of 0.45 to 0.75 µg/kg/week, and 040% with the lower doses (0.075 and 0.225 µg/kg/week).
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For patients receiving s.c. darbepoetin alfa, 45 of 47 patients (96%) experienced at least one adverse event during the study, most of which were mild to moderate in severity. The most frequently reported adverse events were peritonitis (32%), peripheral oedema (30%), injection site pain (30%) and hypertension (30%). These events were typical of those expected in this patient population. Injection site pain and hypertension were the most frequently reported treatment-related adverse events (30 and 17%, respectively).
In general, no difference in the adverse event profile appeared to be attributable to dose cohort assignment or time on study, and no apparent increase in the incidence of adverse events with increased haemoglobin rate of rise was observed. Four patients died on study (three receiving i.v. darbepoetin alfa and one receiving s.c. darbepoetin alfa). All of the deaths were considered by the study investigators to be related to concurrent illness and not to the study drug.
For both the i.v. dosing and the s.c. dosing studies, mean values for vital signs did not change and no clinically meaningful changes in laboratory values were evident. The mean serum ferritin remained well above 100 µg/l throughout the studies, i.e. above the level recommended in the European Best Practice Guidelines [6] and the National Kidney Foundation Dialysis Outcomes Quality Initiative (DOQI) Guidelines [9] for maintenance of adequate iron stores.
No patient in either the i.v. dosing or the s.c. dosing study required a change in dose because of an adverse event. In patients who had their doses of darbepoetin alfa withheld due to a haemoglobin concentration >14 g/dl, the haemoglobin decreased progressively after discontinuation of study drug, and was <12 g/dl by week 5 for patients receiving i.v. therapy and <12 g/dl by week 8 for patients receiving subcutaneous therapy (Figure 4). Most of the patients who required dosing of darbepoetin alfa to be withheld were in the 0.75 µg/kg/week dose group (5/7 patients receiving i.v. therapy and 6/7 patients receiving s.c. therapy).
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Serum darbepoetin alfa levels
Weekly serum trough concentrations of darbepoetin alfa were determined by ELISA throughout the study. Minimal accumulation of the drug was found, with no statistically significant difference in serum levels over time. At weeks 12, 24, 36 and 48, mean serum concentrations were 1.07, 0.58, 1.49 and 0.38 ng/ml during i.v. dosing; and 1.44, 1.54, 0.96 and 1.59 ng/ml during s.c. dosing.
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Discussion |
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These studies were not designed to formally compare once weekly and three-times weekly administration, or to compare the i.v. and s.c. routes of administration. However, there was no apparent difference in haemoglobin response between the two dose schedules, consistent with the known pharmacological properties of darbepoetin alfa and its longer circulating half-life in vivo [12]. Similarly, although there was a slightly greater increase in haemoglobin at the 0.225 µg/kg/week dose level with i.v. compared with s.c. administration, this was not statistically significant, and generally the two routes of administration produced almost identical increases in haemoglobin concentration. This is in contrast to that described previously for rHuEpo, where the dose requirements have generally been lower for s.c. than for i.v. administration [6]. There has been some controversy regarding the effectiveness of once weekly dosing with rHuEpo. Two recent randomized studies found no difference in the weekly dose of s.c. rHuEpo when administered once weekly, when compared with two and three times weekly dosing [13,14]. However, some questions over the study design and analysis methodology have been raised in reaching this conclusion [15]. There is no literature available to support the use of once weekly rHuEpo by the i.v. route.
There were no concerns regarding the safety profile of darbepoetin alfa. Most adverse events were not reported to be related to study drug, and were consistent with common intercurrent events in this patient population. Those adverse events that were reported to be at least possibly related to study drug were similar to those reported previously with rHuEpo, and importantly, no antibodies to darbepoetin alfa were observed in any patients treated for up to 1 year. In the minority of patients in whom the haemoglobin was considered to have increased excessively, and in whom darbepoetin alfa was temporarily stopped, there was a steady decline in haemoglobin over the following 58 weeks. Interestingly, this decrease in haemoglobin was similar for both i.v. and s.c. administration, suggesting that the rate of decline is determined by destruction of circulating red blood cells rather than by drug clearance.
Further randomized studies examining the correction of renal anaemia with darbepoetin alfa compared with rHuEpo have subsequently been conducted. The first of these was in patients with chronic kidney disease not yet requiring dialysis, i.e. chronic renal insufficiency [16], and the second was in chronic kidney disease patients requiring dialysis [17]. The starting dose of darbepoetin alfa in both of these studies was 0.45 µg/kg administered once weekly. The results demonstrated that darbepoetin alfa could safely and effectively increase and maintain haemoglobin concentration within the target range of 1113 g/dl at a reduced dose frequency relative to rHuEpo.
Two further randomized, comparative studies have examined the effect of switching dialysis patients from rHuEpo to darbepoetin alfa [18,19]. Patients on twice or three times weekly rHuEpo were converted to once weekly darbepoetin alfa, and patients on once weekly rHuEpo were converted to darbepoetin alfa once every other week. In the control group, patients carried on their rHuEpo dosing at either once, twice or three times weekly. In both studies, the mean haemoglobin remained stable throughout the study, and there was no significant difference between the treatment groups. The majority of patients (>95%) were able to maintain the reduced dose frequency of darbepoetin alfa throughout the study. The safety profile of darbepoetin alfa was similar to that of rHuEpo. An additional non-comparative study of over 700 dialysis patients has confirmed the ability of darbepoetin alfa to maintain haemoglobin levels at a reduced dosing frequency over a treatment period of 1 year [20].
The data from the studies reported in this paper, along with the other studies described above, confirm the efficacy and safety of darbepoetin alfa as an erythropoietic agent. As the secondary benefits of rHuEpo therapy (in terms of improved quality of life, increased well-being, increased exercise capacity and improved cardiac function) are related to correction of anaemia rather than to the drug itself, it is reasonable to assume that similar secondary benefits would occur with darbepoetin alfa. In serial screening tests, no antibodies against darbepoetin alfa have been detected in this study or any of the other reported studies.
In conclusion, darbepoetin alfa is safe and effective for the treatment of anaemia in patients with chronic kidney disease receiving dialysis. The optimum weekly starting dose appears to be in the range of 0.450.75 µg/kg, and once weekly dosing is possible for both the i.v. and s.c. routes of administration. The potential for a reduced dosing frequency of darbepoetin alfa may have significant advantages for both the patient and the healthcare worker, with a decrease in the number of injections required.
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Contributors |
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Acknowledgments |
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Notes |
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References |
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