This highly efficacious third-generation erythropoiesis-stimulating agent allows compound dosing once monthly in maintenance therapy to stabilise haemoglobin levels in anaemic patients with CKD
Head of the Department
Anaemia associated with chronic kidney disease (CKD) relates to 90% of patients with glomerular filtration rates of 25-30ml/min. It is a well-known cause of high risk of circulatory insufficiency, left-ventricular dysfunction, increased morbidity and mortality due to cardiovascular complications, and prolonged duration of hospitalisations. Besides this, improvement in haematocrit and haemoglobin (Hb) levels significantly influences the quality of life of patients with CKD.
Traditionally applied erythropoietin-stimulating agents (ESAs) are characterised by short half-life and fluctuations in Hb concentrations during treatment. A retrospective analysis of 152,846 haemodialysed patients showed that during a six-month analysis only 6.5% of patients attained a stable Hb level of 11-12.5g/dl, while Hb levels fluctuated in 89.7% of patients. Up to now, most patients treated using ESAs needed dose modification during treatment to maintain stable
Hb levels. However, decrease in Hb levels below 11g/dl is associated with a higher rate of complications and death.[5,6] The new erythropoietin-stimulating drug CERA (continuous erythropoietin receptor activator) is a third-generation agent that has a longer half-life and acts to activate the erythropoietin receptor continuously. CERA is a covalent conjugate of epoetin beta (produced by recombinant DNA technology) and methoxypolyethylene glycol.
CERA’s unique pharmacokinetic properties reduce binding to the erythropoietin receptor and increase receptor dissociation. Its ability to bind to multiple following receptors and its extended half-life guarantee effectiveness and permanent function.[8, 9] Furthermore, after ligand dissociation from the activated receptor complex, internal cell response lasts a few more minutes, indicating that a long-term and constant receptor bond is not necessary for erythropoiesis stimulation. It should be noted that in older-generation ESAs total receptor binding is present (they are characterised by shorter half-life of all unbonded particles, which are eliminated without receptor activation), which does not allow additional receptor activation. In research by Macdougall et al on drug pharmacokinetics in peritoneal dialysed patients, CERA was shown to be the agent with the longest half-life among all registered drugs from the ESA group. Following administration of 0.8μg/kg subcutaneously, drug half-life equalled 139±20 h; after intravenous administration of 0.4μg/kg, drug half-life equalled 134±19 h. Research results pertaining to half-life in patients with CKD were similar to results obtained in healthy individuals; mean drug half-life equalled 130 h after intravenous and subcutaneous administration. The half-life elimination period after intravenous and subcutaneous administration
of CERA is much longer than for other therapeutic options (see Table 1).[11,13,14]
CERA has also been shown to have low clearance, specifically after an administered 0.4μg/kg intravenous dose, while clearance resulted in 0.49±0.06 ml/h/kg. After a 0.8μg/kg dose, results were at 0.90±0.13ml/h/kg. Reticulocyte increase as a response after both intravenous and subcutaneous administration attained a maximum average value after eight days (respectively 73% and 92%), and returned to baseline values after about 21 days. No significant differences in reticulocyte response time were observed using either method of administration. According to the pharmacokinetic
profile of CERA, compared with traditional ESAs, this new drug can be administered at extended intervals and provides conditions for once-a-month administration in anaemia therapy to maintain haemoglobin stability in CKD patients. Maintaining stable values of haemoglobin may have a positive influence by decreasing the incidence of cardiovascular events in these patients.
Studies on the efficacy and safety of CERA have included four phase II and six phase III studies in correction and maintenance treatment (all studies included more than 2,700 patients from 396 centres, 1,789 of them treated with CERA).
Phase II studies included a total of 354 patients (anaemia correction and maintenance in nondialysed and dialysed patients[16-19] and allowed safe and effective initial dosage of 0.6μg/kg administered subcutaneously once every two weeks in the correction phase of renal anaemia treatment in ESA-naive patients (in both dialysed and nondialysed patients). These studies were able to determine that it is possible to prolong intervals between dosages and to determine the dosage for phase III studies – once every two weeks throughout the correction phase, and once a month in the maintenance phase.
Six phase III multicentre studies evaluated the efficacy and safety of CERA in correction[20,21] and maintenance[22-25] anaemia therapy. Response to treatment was defined as an increase in Hb level (minimum 1g/dl from baseline) and concentration of Hb ≥11g/dl (without transfusion of red blood cells). Phase III studies supported the effectiveness of CERA vs epoetin alfa, epoetin beta and darbepoetin alfa with respect to maintaining a stable level of Hb throughout treatment.
Phase III studies demonstrated:
- The effectiveness of an initial dose of 0.6μg/kg once every two weeks in the correction phase, regardless of administration route.
- The effectiveness of CERA as a once-a-month administration in maintenance treatment, regardless of administration route.
- The similar effectiveness of CERA in comparison with previously registered ESA agents (non-inferiority testing), with a comparable safety profile.
- Less frequent Hb values exceeding 13g/dl in the first eight weeks of correction treatment with CERA, in comparison with other ESAs.
- The possibility of administering CERA once a month to patients treated earlier with epoetin one to three times a week, while maintaining a stable Hb value.
- High therapeutic effectiveness independent of age, sex or diabetes status.
Pannier et al found a lower pain intensity while administering CERA vs darbepoietin alfa. Other benefits include reduced workload for nephrology staff due to extended administration intervals. Lower nondirect costs of therapy and improved comfort for patients are of great importance, given that patients receive 152 injections a year in the case of epoetin three times a week, versus similar levels of effectiveness with 12 injections per year (time and motion study submitted).
According to the EMEA label, CERA (tradename Mircera) is administered with a starting dose of 0.6μg/kg once every two weeks in the correction phase; and, after obtaining target Hb level, dosing can be changed to once monthly. Patients currently treated with an ESA can be converted to CERA administration once a month according to three dose categories (see Table 2).
Mircera could be considered an interesting therapeutic option for anaemia in CKD patients.
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