Drugs

, Volume 68, Issue 8, pp 1139–1156

Methoxy Polyethylene Glycol-Epoetin Beta

A Review of its Use in the Management of Anaemia Associated with Chronic Kidney Disease
Adis Drug Evaluation

Summary

Abstract

Methoxy polyethylene glycol-epoetin beta (Mircera®) is a continuous erythropoietin receptor activator, with a long half-life (approximately 130 hours). In patients with anaemia associated with chronic kidney disease (CKD), both on and not on dialysis, who had not previously received an erythropoiesis-stimulating agent (ESA), methoxy polyethylene glycol-epoetin beta administered intravenously or subcutaneously once every 2 weeks resulted in a smooth and steady rise in haemoglobin levels. The response rates were high (up to 97.5%) in these patients at the end of the correction period; response rates with the comparator ESAs (epoetin alfa or beta, or darbepoetin alfa) were up to 96.3%. Moreover, patients with CKD on dialysis who had previously been treated with an ESA maintained stable haemoglobin levels (within ±1 g/dL of baseline and within a range of 10–13.5 g/dL) when directly converted to methoxy polyethylene glycolepoetin beta administered intravenously or subcutaneously once every 2 or 4 weeks. Methoxy polyethylene glycol-epoetin beta is generally well tolerated, with most adverse events being of mild to moderate severity, consistent with the co-morbidities known to occur in this patient group and those reported with other ESAs.

In conclusion, in patients with anaemia associated with CKD, subcutaneous or intravenous methoxy polyethylene glycol-epoetin beta achieved a high haemoglobin response rate (ESA-naive patients) when administered once every 2 weeks and maintained stable haemoglobin levels (patients previously treated with ESAs) when administered once monthly.

Pharmacological Properties

Methoxy polyethylene glycol-epoetin beta is a continuous erythropoietin receptor activator, with a slower association with, but slightly faster dissociation from, the erythropoietin receptor than epoetin beta. Cell stimulation studies demonstrated that this agent has a reduced in vitro, but an increased in vivo, specific activity compared with epoetin beta.

Subcutaneous or intravenous administration of methoxy polyethylene glycolepoetin beta produced a dose-dependent reticulocyte response in patients with CKD that was independent of the frequency of administration.

Following subcutaneous administration of methoxy polyethylene glycol-epoetin beta to anaemic patients with CKD, both on and not on dialysis, maximum serum concentrations (Cmax) occurred after a median 72.0 and 94.5 hours. Times to Cmax after intravenous administration of this agent were 2.0 and 0.25 hours. After subcutaneous administration, absolute bioavailabilities were 62% and 54%, respectively. Haemodialysis had no effect on the serum concentrations of methoxy polyethylene glycol-epoetin beta. Clearance was low (0.49–1.67 mL/h/ kg) and the mean terminal elimination half-life was long (77–142 hours) following subcutaneous or intravenous administration.

Therapeutic Efficacy

Six phase III trials have demonstrated the efficacy of methoxy polyethylene glycol-epoetin beta administered subcutaneously or intravenously once every 2 weeks or once every 4 weeks in patients aged ≥18 years with anaemia associated with CKD, both on and not on dialysis.

In two phase III correction trials in ESA-naive patients with CKD on dialysis (AMICUS study) or not on dialysis (ARCTOS study), haemoglobin response rates in the correction/evaluation period were high (up to 97.5%) in recipients of methoxy polyethylene glycol-epoetin beta administered intravenously (AMICUS) or subcutaneously (ARCTOS) once every 2 weeks. The corresponding response rates were 91.1% with epoetin alfa or beta in AMICUS and 96.3% with darbepoetin alfa in ARCTOS. Methoxy polyethylene glycol-epoetin beta treatment resulted in a smooth and steady rise in haemoglobin levels, with the median time to response being 57 (AMICUS) and 43 (ARCTOS) days in methoxy polyethylene glycol-epoetin beta recipients, 31 days in epoetin alfa recipients (AMICUS) and 29 days in darbepoetin alfa recipients (ARCTOS).

In four phase III maintenance studies (MAXIMA, PROTOS, STRLATA, RUBRA) in patients with CKD on dialysis previously treated with other ESAs (epoetin alfa or beta, or darbepoetin alfa), methoxy polyethylene glycol-epoetin beta administered intravenously (MAXIMA, STRLATA, RUBRA) or subcutaneously (PROTOS, RUBRA) once every 2 or 4 weeks maintained haemoglobin levels within ±1 g/dL of baseline and within a range of 10–13.5 g/dL. The adjusted mean change in haemoglobin level between baseline and the evaluation period (weeks 29–36) in recipients of both methoxy polyethylene glycol-epoetin beta and the comparators was close to zero, demonstrating that little change in haemoglobin levels had occurred. The majority of methoxy polyethylene glycol-epoetin beta recipients (66–76%) and comparator recipients (67–72%) maintained an average haemoglobin level within ±1 g/dL and within a range of 10–13.5 g/dL during the evaluation period. Blood transfusions were required by few recipients of methoxy polyethylene glycol-epoetin beta (6–12%) or the comparator ESAs (8–11%) during the titration/evaluation period.

Pharmacoeconomics

Data obtained from an observational time and motion study conducted in the UK and Germany were used to estimate the potential time and costs saved by converting from comparator ESAs to methoxy polyethylene glycol-epoetin beta in a hypothetical dialysis centre of 100 patients with CKD. With 100% conversion to methoxy polyethylene glycol-epoetin beta, the estimated annual time savings were 37–43 days and annual costs (excluding drug acquisition costs) were estimated to be reduced by up to 59%.

Tolerability

In a pooled analysis of phase II and III trials in patients with anaemia associated with CKD, treatment-related adverse event rates occurred in 6% of methoxy polyethylene glycol-epoetin beta recipients, with hypertension, diarrhoea and nasopharyngitis being the most commonly reported adverse events. Most adverse events were mild to moderate in severity, and were consistent with the co-morbidities known to occur in this patient group. Serious adverse events occurred in a similar percentage of recipients of methoxy polyethylene glycol-epoetin beta and comparator ESAs (37% vs 40%). The proportion of patients who died in the randomized phase III population was 5.7% in the methoxy polyethylene glycolepoetin beta group and 6.1% in the comparator group.

Platelet levels were lower with methoxy polyethylene glycol-epoetin beta than comparator treatment, but remained within the normal range. Platelet counts <100 × 109/L were reported in 7% of methoxy polyethylene glycol-epoetin beta recipients and 4% of recipients of the comparators.

No clinically relevant changes in vital signs, iron levels or laboratory parameters were reported during the phase LU studies. No antibodies to methoxy polyethylene glycol-epoetin beta were detected during the clinical trial programme.

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Copyright information

© Adis Data Information BV 2008

Authors and Affiliations

  1. 1.Wolters Kluwer Health ¦ AdisMairangi Bay, North Shore 0754, AucklandNew Zealand
  2. 2.Wolters Kluwer HealthConshockenUSA

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