Introduction
Erythropoietin (EPO) is a hormone that is
predominantly produced by the kidneys. It acts on the bone marrow
to stimulate the proliferation and differentiation of red blood
cells. In 1989, the first recombinant EPO (rEPO) preparation,
epoetin-α, was approved by the US Food and Drug Administration for
the treatment of anemia associated with kidney disease (1,2).
Since then, several clinically approved rEPO preparations, such as
epoetin-β, epoetin-δ and the epoetin-α derivative, darbepoietin-α,
have been commercially produced. Since the expiration of patent
protection, a number of novel rEPO biosimilars have been approved
on the world market. In 2010, epoetin-κ, which is biosimilar to
epoetin-α, was clinically approved in Japan (3). Epoetin-κ is a biopharmaceutical
product that is based on serum-free media following master cell
bank preparation. In general, and as is the case with this
medicine, the manufacture of treatments based on genetic
recombination that utilize animal cells requires the use of
adhesive cells to function as the serum constituent (4). As a result, it is not easy to obtain
cells with steady levels of productivity from a non-blood serum
that is created only from a general culture medium (2–4).
However, the preparation for epoetin-κ involves a new manufacturing
method, being cultivated using a bloodless liquid medium and a
purification process that does not utilize animal byproducts. It
has been indicated that epoetin-κ exhibits the same efficacy as a
preparation of erythropoietin, which, to date, has been used with a
basic three-times-a-week administration, resulting in the
demonstration of its safety and quality (5–7).
The present study examined a cohort of patients
receiving chronic dialysis who were clinically in a state of
relative calm and whose renal anemia was well controlled. The
ability to sustain good control of the anemia when the frequency of
the epoetin-β administration was reduced from the conventional and
empirically determined three times a week to twice a week, and
further to once a week (8,9) was assessed. Furthermore, the ability
to maintain good control upon switching from epoetin-β to epoetin-κ
was investigated. The impact of the change, including the economic
effect, was also considered.
Patients and methods
Thirty patients were maintained at The Kan-Etsu
Hospital (Tsurugashima, Japan) on dialysis, with an epoetin dosing
frequency of once or twice a week. The clinical parameters of the
patients that were associated with anemia (red blood cell counts,
hemaglobin and hematocrit) were obtained over a six-month period,
during which the administration of epoetin-β was changed to that of
epoetin-κ. The clinical parameters collected in the three months
prior to and following the switch, respectively, were subsequently
compared. Males accounted for a large proportion of the patients
(26) and 16 of those males were aged ≥65 years (Table I). There were eight patients with
underlying diabetes (Table I). The
frequency of drug administration for the 30 patients was twice a
week or less. Monthly blood samples were obtained from the patients
in the three months prior to and following the changeover from
epoetin-β to epoetin-κ, for six months in total. The differences in
the fluctuations between the clinical parameters prior to and
following the change were subsequently examined. When examining the
changes following the switch from epoetin-β to epoetin-κ, the
patients were divided into three groups (9): N-N, L and H. Group N-N comprised
patients whose hemoglobin (Hb) levels ranged between 10 and 12 g/dl
prior to and following the change from epoetin-β to epoetin-κ;
group L comprised patients whose Hb levels decreased to <10 g/dl
at least once prior to the change to epoetin-κ; and group H
comprised patients whose Hb levels increased to >12 g/dl at
least once prior to the change to epoetin-κ. The frequency and dose
of epoetin administration differed among the patients, with a dose
of 750 units administered once a week in seven cases, twice a week
in 14 cases and once every two weeks in one case; a dose of 1,500
units administered once a week in two cases and twice a week in
five cases; and a dose of 3,000 units administered twice a week in
one case (Table II).
 | Table IGeneral patient data. |
Table I
General patient data.
| Characteristic | Cases [n (%)] |
|---|
| Gender |
| Male | 26 (86.7) |
| Female | 4 (13.3) |
| Agea (years) |
| <65 | 14 (46.7) |
| ≥65 | 16 (53.3) |
| Origin |
| Diabetes | 8 (26.7) |
| Polycystic
kidney | 6 (20.0) |
| IgA nephritis | 1 (3.3) |
| CGN | 11 (36.7) |
| Other | 4 (13.3) |
| HD term (years) |
| <10 | 19 (63.3) |
| ≥10 | 11 (36.7) |
| Table IIInjection frequency and dose of
patients. |
Table II
Injection frequency and dose of
patients.
| Dose (IU) |
|---|
|
|
|---|
| Frequency | 750 (n) | 1500 (n) | 3000 (n) |
|---|
| Once a week | 7 | 2 | 0 |
| Twice a week | 14 | 5 | 1 |
| Every other week | 1 | 0 | 0 |
Results
As the most common dose among the case group, 750
units epoetin was administered once or twice a week and an
examination of the changes of each average parameter was conducted,
based on the average of the seven and 14 cases receiving this dose,
respectively. The results of this analysis revealed that there was
little fluctuation in the data prior to and following the
switchover. It was concluded that the administration of ≥750 units
of epoetin-β or epoetin-κ once or twice a week was appropriate from
a clinical standpoint.
The changes in Hb levels are shown graphically in
Fig. 1. Prior to switching to
epoetin-κ, a reduction in the Hb levels was observed; however, the
levels were predominantly stable over the period of observation.
The changes in clinical parameters following the switch were also
examined in the patient groups N-N, L and H. Following the change
from epoetin-β to epoetin-κ, the Hb levels in each group remained
at ~11 g/dl (Fig. 2), while the
hematocrit (Ht) remained at ~35% (Fig.
3) and the red blood cell counts appeared to converge at
350×104/μl (Fig.
4).
Discussion
As standard formulations for the administration of
<250 units of epoetin-β and -κ were not available in the present
study, the anemia was controlled by decreasing the administration
frequency of the drug. With regard to cases where 3,000 units of
formulation are administered to maintain symptom control, it may be
considered preferable to administer the drug twice a week at the
same dose, rather than three times a week at a lower dose of 1,500
units, owing to the lower number of administrations per week.
The basic manufacturing patent for the materials
used to manufacture rEPO expired in 2005 and, as such, there are no
longer any restrictions on its development (5,6,11).
Therefore, it is expected that rEPO will be manufactured with a
high level of safety through processes that do not use animal
byproducts. With regard to its usage and dosage, the treatment
guidelines recommend that it be administered three times a week
(9). However, following the
enforcement of comprehensive coverage for the costs of dialysis
treatment at medical facilities in 2006, it has been recommended
that, in order to maintain the Hb standard value, the majority of
patients may be expected to stably respond to an administration of
1,500 units three times a week or 3,000 units twice a week, while
additional dosage restrictions are also expected (12). During phases II and III of its
clinical trials, an evaluation was performed that involved
switching from epoetin-α to this drug and, in this instance, the
dosage was 1,500 or 3,000 units twice or three times a week
(13). However, as it is expected
that administrations at lower doses and lower frequencies are
likely to be conducted in clinical settings, The Kan-Etsu Hospital
has been proactively studying alternative dosages and has evaluated
the equivalence of this drug with its predecessor drugs at dosages
not used in phases II and III of its clinical trials. In a study
conducted in 1998 (14), it was
demonstrated that there was a correlation between the weekly rate
of change in Hb levels and the frequency of adverse events.
Furthermore, it was shown that the greater the degree of
instability and the greater the decline, the higher the frequency
of adverse events. In the study performed by Fishbane and Berns
(15), the term ‘Hb Cycling’ was
applied to the phenomenon in which fluctuations >1.5 g/dl in
their degree of instability (observed for one year) repeated
themselves in an eight-week cycle (15). In another study, Ebben et
al(10) conducted a
retrospective analysis of 150,000 patients receiving dialysis
(10). Dividing the patients into
three groups, ‘Target’, ‘High’ and ‘Low’, according to their Hb
levels (similar to this experiment), the fluctuation patterns in Hb
levels were observed. The results indicated that, irrespective of
the time of occurrence, the proportion of cases included in the
Target Group did not reach 50%.
The present study yielded results obtained during a
six-month observation period, during which the administration of
epoetin-β was changed to that of to epoetin-κ. Three months
following the switch to epoetin-κ, the degree of instability had
decreased. Although the situation subsequent to the change from
epoetin-β to epoetin-κ requires further investigation, it may be
concluded that the results obtained in this study are indicative of
the clinical equivalence and the efficacy of epoetin-κ.
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