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Memantine

A Review of its Use in Alzheimer’s Disease

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Summary

Abstract

Memantine (Ebixa®, Axura®, Namenda®, Akatinol®) is a moderate-affinity, uncompetitive, voltage-dependent, NMDA-receptor antagonist with fast on/off kinetics that inhibits excessive calcium influx induced by chronic overstimulation of the NMDA receptor. Memantine is approved in the US and the EU for the treatment of patients with moderate to severe dementia of the Alzheimer’s type.

In well designed clinical trials, oral memantine, as monotherapy or in addition to a stable dose of acetylcholinesterase inhibitors, was well tolerated during the treatment of mild to severe Alzheimer’s disease for up to 52 weeks. Memantine generally modified the progressive symptomatic decline in global status, cognition, function and behaviour exhibited by patients with moderate to severe Alzheimer’s disease in four 12- to 28-week trials. In patients with mild to moderate Alzheimer’s disease, data from three 24-week trials are equivocal, although meta-analyses indicate beneficial effects on global status and cognition. Memantine is an effective pharmacotherapeutic agent, and currently the only approved option, for the treatment of moderate to severe Alzheimer’s disease.

Pharmacological Properties

Memantine is an uncompetitive antagonist that blocks the NMDA channel with higher affinity, but less voltage-dependency, than magnesium. It moderately inhibits excitatory activity while preserving learning behaviours in vivo when compared with more potent NMDA receptor channel blockers. During pathological activation of the NMDA receptor, memantine blocks excessive calcium entry through the channel and is neuroprotective in in vitro and in vivo models.

Oral memantine is completely absorbed with an absolute bioavailability of ≈100%. Steady-state plasma concentrations, achieved after about 2 weeks of memantine 20 mg/day, range from 70 to 150 gmg/L, while the steady-state area under the plasma concentration-time curve from time 0 to 24 hours is ≈1800 gmg · h/L after 4 weeks of treatment.

Memantine is excreted in urine mostly as unchanged parent drug with the remainder being metabolised by glucuronidation, hydroxylation and N-oxidation to form NMDA-inactive metabolites. Memantine and its metabolites are primarily eliminated by the kidneys with a terminal elimination half-life of 60–100 hours. Total renal clearance in healthy volunteers is 170 mL/min/1.73m2.

Therapeutic Efficacy

The efficasy of memantine 20 mg/day has been examined in seven randomised, double-blind, placebo-controlled, multicentre trials of 12–28 weeks’ duration in patients with mild to severe Alzheimer’s disease.

In two of four trials in patients with moderate to severe Alzheimer’s disease, intent-to-treat analyses indicated that global status was significantly better with memantine than with placebo, either as monotherapy or in addition to a stable dose of donepezil. In a third trial, while global status did not differ significantly based on intent-to-treat analysis, observed-case analysis favoured memantine over placebo. However, preliminary data from a fourth trial indicate numerical differences between memantine and placebo treatment groups that were not significant.

In patients with moderate to severe Alzheimer’s disease, memantine or donepezil plus memantine also maintained superior cognitive performance and function with respect to placebo or placebo plus donepezil in two of the three trials in which they were assessed, and superior behaviour in two of the four trials.

In one published trial in patients with mild to moderate Alzheimer’s disease, memantine monotherapy significantly attenuated the decline in global status and cognition observed in placebo recipients; however, in preliminary data from another monotherapy trial, significantly greater effects with memantine seen at 12 and 18 weeks were lost at trial end, apparently as a result of an improvement in global status and cognition in placebo recipients in the last weeks of the trial. Initial results of a third study in this patient population, with memantine or placebo added to a stable dose of an acetylcholinesterase inhibitor, indicate a numerical difference that was not significant.

Meta-analyses indicate significant effects of memantine on global status, cognition and function in patients with mild to severe Alzheimer’s disease, and on global status, cognition, function and behaviour in patients with moderate to severe Alzheimer’s disease.

Tolerability

Memantine was generally well tolerated with a good safety profile during clinical trials, most adverse events being of mild or moderate severity. Adverse events were reported by 70% of patients receiving either memantine or placebo, but most were not considered drug related. In pooled analyses, memantine was associated with a higher incidence of dizziness, headache, constipation and somnolence than placebo. Serious adverse events occurred in 12.7% of memantine and 13.8% of placebo recipients.

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Notes

  1. The use of trade names is for identification purposes only and does not imply endorsement.

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Authors and Affiliations

  1. Adis International Limited, 41 Centorian Drive, Private Bag 65901, Mairangi Bay, Auckland, 1311, New Zealand

    Dean M. Robinson & Gillian M. Keating

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  1. Dean M. Robinson
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Various sections of the manuscript reviewed by: S. Bleich, Klinik mit Poliklinik für Psychiatrie und Psychotherapie, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany; R. Cacabelos, EuroEspes Biomedical Research Center, Santa Marta de Babio, La Coruna, Spain; M.R. Farlow, Department of Neurology, Indiana University School of Medicine, Indianapolis, Indiana, USA; R. McShane, Cochrane Dementia and Cognitive Improvement Group, Fulbrook Centre, Churchill Hospital, Oxford, England; J.J. Miguel-Hidalgo, Department of Psychiatry and Human Behavior, University of Mississippi Medical Center, Jackson, Mississippi, USA; F.A. Schmitt, Department of Neurology, Sanders-Brown Center on Aging, University of Kentucky Medical Center, Lexington, Kentucky, USA; R.R. Tampi, Geriatric Services, Yale New Haven Psychiatric Hospital, New Haven, Connecticut, USA; C.H. van Dyck, Department of Psychiatry and Neurobiology, Yale University, New Haven, Connecticut, USA; G.L. Wenk, Departments of Psychology and Neurology, Division of Neural Systems, Memory and Aging, University of Arizona, Tucson, Arizona, USA; A. Wimo, Aging Research Centre, Neurotec Department, Karolinska Institutet, Stockholm, Sweden.

Data Selection

Sources: Medical literature published in any language since 1980 on memantine, identified using MEDLINE and EMBASE, supplemented by AdisBase (a proprietary database of Adis International). Additional references were identified from the reference lists of published articles. Bibliographical information and unpublished contributory data was also requested from the company developing the drug.

Search strategy: MEDLINE, EMBASE and AdisBase search terms were ‘memantine’. Searches last updated 7 August 2006.

Selection: Studies in patients with Alzheimer’s disease who received memantine. Inclusion of studies was based mainly on the methods section of the trials. When available, large, well controlled, peer reviewed trials with appropriate statistical methodology were preferred. Relevant pharmacodynamic and pharmacokinetic data are also included.

Index terms: Memantine, Alzheimer’s disease, dementia, pharmacodynamics, pharmacokinetics, therapeutic use.

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Robinson, D.M., Keating, G.M. Memantine. Drugs 66, 1515–1534 (2006). https://doi.org/10.2165/00003495-200666110-00015

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