Memantine A Review of its Use in Moderate to Severe Alzheimer's Disease

Memantine is an uncompetitive, moderate-affinity NMDA receptor antagonist that is indicated for the treatment of moderate to severe Alzheimer's disease. In well designed trials in patients with moderate to severe Alzheimer's disease, oral memantine monotherapy improved outcomes in the area of functional ability more than placebo in one trial, but in a second trial, treatment differences did not reach significance. Memantine has a distinct mode of action compared with that of acetylcholinesterase (AChE) inhibitors, and in a well designed study, combination therapy with memantine plus donepezil improved outcomes more than donepezil plus placebo in all four domains (function, cognition, behaviour and global change). Memantine is generally well tolerated, with adverse events occurring with a similar incidence to that reported with placebo. In modelled cost-effectiveness analyses, memantine was dominant to no therapy in regard to cost per quality-adjusted life-year (QALY) gained, and the combination of memantine plus donepezil was dominant to donepezil therapy alone in regard to QALYs gained when treatment periods exceeded I year in patients with moderate to severe disease. Thus, in the management of patients with moderate to severe Alzheimer's disease, memantine provides an effective treatment option. To date, clinical trial support is greater for memantine use in combination with an AChE inhibitor, while more data are needed to confirm its efficacy as monotherapy. Pharmacological Properties Memantine is an uncompetitive (open-channel), moderate-affinity NMDA receptor antagonist, with strong voltage dependency and rapid blocking and unblocking kinetics. The blocking of the NMDA channel modulates the effects of pathologically elevated tonic levels of the neurotransmitter glutamate that may lead to neuronal dysfunction. Memantine reduces NMDA-induced excitotoxicity, but still allows receptor signalling for physiological activation. Oral memantine is completely absorbed, with an absolute bioavailability of about 100%. Linear pharmacokinetics were observed over the therapeutic dose range. At steady state, plasma memantine concentrations ranged from 70 to 150 ng/mL, with large interindividual differences. The mean volume of distribution is about 10 L/kg, and about 45% of the drug is bound to plasma proteins. Memantine is converted primarily to three polar metabolites, which have minimal NMDA receptor antagonist activity. Memantine and its metabolites are primarily excreted by the kidneys. Total renal clearance in healthy volunteers was 170mL/min/1.73m(2). The terminal elimination half-life of memantine is about 60-100 hours. Therapeutic Efficacy In one well designed study of memantine 20 mg/day monotherapy for 6 months, the outcome of one primary efficacy measure (function) was significantly better with memantine than placebo, but the difference between treatment groups did not reach significance for the other primary endpoint (global change). Secondary endpoints of cognitive performance, dementia progression and the need for caregiver time showed significantly less decline with memantine than with placebo. In a 6-month, nonblind extension phase, patients switched to memantine had a significantly slower rate of decline than that recorded when they received placebo. In a second well designed, 6-month trial, the difference in efficacy between memantine and placebo did not reach statistical significance for either co-primary endpoint. The efficacy of memantine combined with the AChE inhibitor donepezil in a well designed, 6-month trial was significantly better than that of donepezil plus placebo for both primary endpoints (domains of function and cognitive performance), as well as in secondary global, behavioural and care dependency assessments. Better outcomes were also associated with combination therapy than with AChE inhibitor therapy or standard care alone over 30 months' treatment. Meta-analyses of randomized controlled trials of about 6 months duration indicate that memantine alone or in combination with stable AChE inhibitor treatment generally improves outcomes in patients with moderate to severe Alzheimer's disease across all four domains (global change, cognition, function and behaviour). Cost-effectiveness analyses indicate that memantine is dominant to no pharmacotherapy in patients with moderate to severe Alzheimer's disease for treatment periods of 2-5 years in regard to the cost per QALY gained. Compared with monotherapy with donepezil, combination therapy with memantine plus donepezil was associated with a incremental cost-effectiveness ratio of $US382 per QALY gained over 1 year, but for periods greater than 1 year, combination therapy was dominant to donepezil alone. Tolerability Memantine was generally well tolerated when used alone or in combination with AChE inhibitors in patients with moderate to severe Alzheimer's disease. In clinical trials, most adverse events were mild to moderate in severity and were not related (or not likely to be related) to study medication. The incidence of adverse events with memantine (74-84%) was not different from that with placebo (73-87%) in 6-month trials, and the most common event was agitation, which occurred less with memantine than with placebo. The tolerability profile of memantine during long-term (up to 1 year) therapy was similar to that observed over 6 months. There were no clinically relevant changes in laboratory tests, vital signs and electrocardiogram measurements compared with baseline associated with memantine during 6- and 12-month studies.