Mircera Mechanism of Action

Therapeutic/Pharmacologic Class of Drug: MIRCERA is the first molecule of a new class of Continuous Erythropoietin Receptor Activators called methoxy polyethylene glycol-epoetin beta. ATC Code: B03XA03.
PHARMACOLOGY: Pharmacodynamics: MIRCERA is a chemically synthesized continuous erythropoietin receptor activator. Methoxy polyethylene glycol-epoetin beta differs from erythropoietin through integration of an amide bond between either the N-terminal amino group or the ε-amino group of lysine, predominantly Lys⁵² and Lys⁴⁵ and methoxy polyethylene glycol butanoic acid. This results in a molecular weight of approximately 60,000 daltons for methoxy polyethylene glycol-epoetin beta with the PEG-moiety having an approximate molecular weight of 30,000 daltons.
In contrast with erythropoietin, MIRCERA shows a different activity at the receptor level characterized by a slower association to and faster dissociation from the receptor, a reduced specific activity in vitro with an increased activity in vivo, as well as an increased half-life. These differential pharmacological properties are relevant in order to achieve a once monthly dosing regimen with MIRCERA in patients.
Mechanism of Action: MIRCERA stimulates erythropoiesis by interaction with the erythropoietin receptor on progenitor cells in the bone marrow. As primary growth factor for erythroid development, the natural hormone erythropoietin is produced in the kidney and released into the bloodstream in response to hypoxia. In responding to hypoxia, the natural hormone erythropoietin interacts with erythroid progenitor cells to increase red cell production.
Clinical/Efficacy Studies: Adult Patients: In two randomized controlled studies in CKD patients not on dialysis BA16738 and NH20052, MIRCERA achieved correction of anemia in 97.5% and 94.1% of patients, respectively. During the first 8 weeks of treatment the proportion of patients experiencing a haemoglobin level greater than 13 g/dL was 11.4% in the MIRCERA group and 34% in the darbepoetin alfa group in study BA16738, while the corresponding proportions of patients experiencing a haemoglobin level greater than 12 g/dL were 25.8% in the MIRCERA group and 47.7% in the darbepoetin alfa group in NH20052. In a randomized controlled study in CKD patients on dialysis, MIRCERA achieved correction of anemia in 93.3% of patients.
Four randomized controlled studies were performed in dialysis patients currently treated with darbepoetin alfa or epoetin. Patients were randomized to stay on their current treatment or to be converted to MIRCERA in order to achieve stable haemoglobin levels. At the evaluation period (week 29 to 36), the mean and median level of haemoglobin in patients treated with MIRCERA was virtually identical to the baseline haemoglobin level.
In a controlled, open label, multi-centre study, 490 patients (245 per treatment arm) were randomized to compare the efficacy and safety of MIRCERA with that of darbepoetin alfa for the maintenance treatment of anemia in patients with CKD who are on hemodialysis.
The proportion of responders was significantly higher in patients treated with MIRCERA once-monthly than with darbepoetin alfa once-monthly (p<0.0001). Of the 245 patients in each group, 157 (64.1%) in the MIRCERA group were responders compared to 99 (40.4%) in the darbepoetin alfa group. Response was defined as patients with an average Hb >10.5 g/dL and an average decrease from individual baseline not exceeding 1.0 g/dL during the evaluation period.
Paediatric Patients: A phase II, dose-finding, open-label, multiple dose, multicenter study was conducted in 64 paediatric patients (aged 5-17 years old) with CKD who were on hemodialysis, to determine the effective starting dose of MIRCERA IV when switching from maintenance treatment with another ESA (epoetin alfa/beta or darbepoetin alfa). The primary efficacy endpoint in this study (change in Hb concentration (g/dL) between the baseline and evaluation periods) has been met. Overall, the adverse event profile observed was consistent with the safety profile in adults.
Pharmacokinetics: In patients, the pharmacokinetic and the pharmacologic properties allow monthly administration of MIRCERA due to the long elimination half life. The elimination half-life after IV administration of MIRCERA is 15 to 20 times longer compared to recombinant human erythropoietin.
The pharmacokinetics of MIRCERA were studied in healthy volunteers and in anemic patients with CKD including patients on dialysis and not on dialysis.
In CKD patients, clearance and volume of distribution of methoxy polyethylene glycol-epoetin beta were not dose dependent.
In CKD patients, the pharmacokinetics of MIRCERA were studied after the first dose and after administrations on week 9 and on week 19 or 21. Multiple dosing had no effect on clearance, volume of distribution and bioavailability of methoxy polyethylene glycol-epoetin beta. After administration every 4 weeks in CKD patients, there was no meaningful accumulation of methoxy polyethylene glycol-epoetin beta, as demonstrated by a ratio of accumulation of 1.03. After administration every 2 weeks, the ratio of accumulation was 1.12.
A comparison of serum concentrations of methoxy polyethylene glycol-epoetin beta measured before and after haemodialysis in 41 CKD patients showed that haemodialysis has no effect on the pharmacokinetics of methoxy polyethylene glycol-epoetin beta.
An analysis in 126 CKD patients showed no pharmacokinetic difference between patients on dialysis and patients not on dialysis.
The results of a study in 42 healthy volunteers indicated that the site of subcutaneous injection (abdomen, arm or thigh) has no clinically relevant effect on the pharmacokinetics, pharmacodynamics or local tolerability of MIRCERA. Based on these results, all three sites are considered suitable for subcutaneous injection with MIRCERA.
Absorption: Absorption after subcutaneous administration: Following SC administration to CKD patients, the maximum serum concentrations of methoxy polyethylene glycol-epoetin beta were observed 72 hours (median value) after administration in dialysis patients and 95 hours after administration in patients not on dialysis.
The absolute bioavailability of methoxy polyethylene glycol-epoetin beta after SC administration was 62% and 54%, in dialysis patients and patients not on dialysis, respectively.
Distribution: A study in 400 CKD patients showed that the volume of distribution of methoxy polyethylene glycol-epoetin beta is approximately 5 L.
Metabolism: No data to report.
Elimination: Following IV administration to CKD patients, the t_½ for methoxy polyethylene glycol-epoetin beta was 134 hours [or 5.6 days], and the total systemic clearance was 0.494 mL/h per kg. Following SC administration the observed terminal elimination half-life (t_½) was 139 hours in dialysis patients and 142 hours in patients not on dialysis.
Pharmacokinetics in Special Populations: Hepatic Impairment: The pharmacokinetics of MIRCERA are similar in patients with severe hepatic impairment as compared to healthy subjects (see Special Dosage Instructions under Dosage & Administration).
Paediatric Population: The pharmacokinetics of MIRCERA were studied in 64 paediatric CKD patients (aged 5-17 years old) receiving hemodialysis. At steady state (following the third IV administration of MIRCERA) the maximum observed exposures were a geometric mean C_max of 66.1 ng/mL and a geometric mean AUC_0-tau of 7170 ng.hr/mL. Subsequently, Mircera serum concentrations declined with an apparent mean half-life of approximately 121 to 147 hours (geometric mean) comparable to adults.
Other special populations: Population analyses evaluated the potential effects of demographic characteristics on the pharmacokinetics of MIRCERA. Results of these analyses showed that no adjustments of the starting dose are necessary for age (>18 years), gender, or race. The population pharmacokinetic analysis also showed no pharmacokinetic differences between patients on dialysis and patients not on dialysis.
Toxicology: Preclinical Safety: Carcinogenicity: The carcinogenic potential of MIRCERA has not been evaluated in long-term animal studies. MIRCERA did not induce a proliferative response in non-haematological tumor cell lines in vitro. In a six-month rat toxicity study no tumorigenic or unexpected mitogenic responses were observed in non-haematological tissues. In addition, using a panel of human tissues, the in vitro binding of MIRCERA was only observed in target cells (bone marrow progenitor cells).
Mutagenicity: No data to report.
Impairment of Fertility: When MIRCERA was administered subcutaneously to male and female rats prior to and during mating, reproductive performance, fertility, and sperm assessment parameters were not affected.
Teratogenicity: Studies in animals have not shown any harmful effect of MIRCERA on pregnancy, embryonal/foetal development, parturition or postnatal development.
Other: No data to report.