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Mircera

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Mircera

Mircera

CLINICAL PHARMACOLOGY

Mechanism of Action

Mircera (methoxy polyethylene glycol-epoetin beta) is an erythropoietin receptor activator with greater activity in vivo as well as increased half-life, in contrast to erythropoietin. A primary growth factor for erythroid development, erythropoietin is produced in the kidney and released into the bloodstream in response to hypoxia. In responding to hypoxia, erythropoietin interacts with erythroid progenitor cells to increase red cell production. Production of endogenous erythropoietin is impaired in patients with chronic renal failure (CRF) and erythropoietin deficiency is the primary cause of their anemia.

Pharmacodynamics

Following a single, dose of Mircera (methoxy polyethylene glycol-epoetin beta) in CRF patients, the onset of hemoglobin increase (defined as an increase > 0.4 g/dL from baseline) was observed 7 to 15 days following initial dose administration [see DOSAGE AND ADMINISTRATION].

Pharmacokinetics

The pharmacokinetics of Mircera (methoxy polyethylene glycol-epoetin beta) were studied in anemic patients with CRF including patients on dialysis and not on dialysis. Mircera (methoxy polyethylene glycol-epoetin beta) pharmacokinetics, based on population analyses, were not altered by age, gender, race, or the use of dialysis.

Following an IV administration of Mircera (methoxy polyethylene glycol-epoetin beta) 0.4 mcg/kg body weight to CRF patients receiving peritoneal dialysis, the observed terminal half-life was 134 ± 65 hours (mean ± SD), and the total systemic clearance was 0.49 ± 0.18 mL/hr/kg. Following a SC administration of Mircera (methoxy polyethylene glycol-epoetin beta) 0.8 mcg/kg to CRF patients receiving peritoneal dialysis, the terminal half-life was 139 ± 67 hours. The maximum serum concentrations of Mircera (methoxy polyethylene glycol-epoetin beta) were observed 72 hours (median value) following the SC administration. The absolute bioavailability of Mircera (methoxy polyethylene glycol-epoetin beta) after the SC administration was 62%.

In CRF patients receiving multiple Mircera (methoxy polyethylene glycol-epoetin beta) doses, pharmacokinetics were studied after the first dose and on week 9 and week 19 or 21. Multiple dosing was found to have no effect on clearance, volume of distribution or bioavailability of Mircera (methoxy polyethylene glycol-epoetin beta) . Based on population analyses of the clinical studies, Mircera (methoxy polyethylene glycol-epoetin beta) did not accumulate following administration every four weeks. However, when Mircera (methoxy polyethylene glycol-epoetin beta) was administered every 2 weeks, blood concentrations at steady state increased by 12%.

A comparison of serum concentrations of Mircera (methoxy polyethylene glycol-epoetin beta) measured before and after hemodialysis in 41 patients showed that hemodialysis did not alter serum concentrations.

The site of SC injection (abdomen, arm or thigh) had no clinically important effects on the pharmacokinetics or pharmacodynamics of Mircera (methoxy polyethylene glycol-epoetin beta) in healthy volunteers.

Clinical Studies

The efficacy and safety of Mircera (methoxy polyethylene glycol-epoetin beta) were assessed in six open-label, multi-center clinical studies that randomized patients to either Mircera (methoxy polyethylene glycol-epoetin beta) or a comparator ESA. Two studies evaluated anemic patients with CRF who were not treated with an ESA at baseline and four studies evaluated patients who were receiving an ESA for treatment of the anemia of CRF. In all studies, patients were assessed as clinically stable at baseline and without evidence of infection or inflammation as determined by history and laboratory data, including C-reactive protein (CRP ≤ 15 mg/L for study 1 and CRP ≤ 30 mg/L for studies 2 to 6). A CRP value above the threshold led to the exclusion of no more than 3% of the screened patients.

In the clinical studies, ESAs were administered to achieve specific hemoglobin levels (see Table 4 and Table 5). Following stabilization of hemoglobin levels (12 g/dL), the median monthly Mircera (methoxy polyethylene glycol-epoetin beta) dose was 150 meg (range of 97 meg to 270 meg).

Patients Not Currently Treated with an ESA

In Study 1 patients who were not receiving dialysis were randomized to Mircera (methoxy polyethylene glycol-epoetin beta) or darbepoetin alfa, administered for 28 weeks. The starting dose of Mircera (methoxy polyethylene glycol-epoetin beta) was 0.6 meg/kg administered SC once every two weeks and the starting dose of darbepoetin alfa was 0.45 meg/kg administered SC once a week. In Study 2, patients who were receiving dialysis were randomized to Mircera (methoxy polyethylene glycol-epoetin beta) or another ESA (Epoetin alfa or Epoetin beta), administered for 24 weeks. The starting dose of Mircera (methoxy polyethylene glycol-epoetin beta) was 0.4 meg/kg administered IV once every two weeks and the starting dose of the comparator was administered IV three times a week, consistent with the product's recommended dose. In these studies, the observed median dose of Mircera (methoxy polyethylene glycol-epoetin beta) once every two weeks over the course of the correction/evaluation period was 0.6 meg/kg. Table 4 provides the results of the two studies.

Table 4: Clinical Studies in Patients Not Currently Treated with an ESA


Group
(n)
Percent Achieving
Goal* (95% CI)
Mean
Hemoglobin
Change from
Baseline (g/dL)
RBC Transfusion, %
Studv 1
Mircera
(n=162)
98 (94, 99) 2.1 2.5
Darbepoetin alfa
(n=162)
96 (92, 99) 2.0 6.8
Study 2
Mircera
(n=135)
93 (88, 97) 2.7 5.2
Epoetin alfa/beta
(n=46)
91 (79, 98) 2.6 4.3
*Uoal: hemoglobin increase of at least 1 g/dL and to a level of at least 11 g/dL without RBC transfusion; hemoglobin levels were to be maintained within the range of 11 to 13 g/dL.
Patients Currently Treated with an ESA

Four studies assessed the ability of Mircera (methoxy polyethylene glycol-epoetin beta) to maintain hemoglobin concentrations among patients currently treated with other ESAs. Patients were randomized to receive Mircera (methoxy polyethylene glycol-epoetin beta) administrations either once every two weeks or once every four weeks, or to continue their current ESA dose and schedule. The initial Mircera (methoxy polyethylene glycol-epoetin beta) dose was determined based on the patient's previous weekly ESA dose. As shown in Table 5, treatment with Mircera (methoxy polyethylene glycol-epoetin beta) once every two weeks and once every four weeks maintained hemoglobin concentrations within the targeted hemoglobin range (10 to 13.5 g/dL).

Table 5: Clinical Studies in Patients Currently Treated with an ESA


Group
(n)
Mean Baseline
Hemoglobin
Evaluation
Period
Hemoglobin
(Mean)
Between-group
Difference *,
g/dL (95% or 97.5% CI)
Study 3
Mircera IV every 2 weeks (n=223) 12.0 11.9 0.0 (-0.2, 0.2)
Mircera IV every 4 weeks (n=224) 11.9 11.9 0.1 (-0.2, 0.3)
Epoetin alfa/beta IV (n=226) 12.0 11.9 n/a
Study 4
Mircera SC every 2 weeks (n=190) 11.7 11.7 0.1 (-0.1, 0.4)
Mircera SC every 4 weeks (n=191) 11.6 11.5 -0.0 (-0.3, 0.2)
Epoetin beta SC (n=191) 11.6 11.5 n/a
Study 5
Mircera, IV every 2 weeks (n=157) 12.0 12.1 0.2 (-0.0, 0.4)
Darbepoetin alfa IV (n=156) 11.9 11.8 n/a
Study 6
Mircera IV/SC every 2weeks(n= 68) 11.8 11.9 0.1 (-0.1, 0.4)
Epoetin alfa IV/SC (n=168) 11.9 11.8 0.1 (-0.1,0.4)
*Mircera versus comparator mean hemoglobin difference in the evaluation period; 97.5% CI are shown for studies that compared two Mircera groups to another ESA (Studies 3 and 4) and 95% CI are shown for the other studies. n/a = not applicable

Last reviewed on RxList: 12/20/2007
This monograph has been modified to include the generic and brand name in many instances.

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