Memantine
Memantine is an uncompetitive NMDA receptor antagonist, and thus relies on glutamate's activation of the NMDA receptor to take effect.[29] Designed to block pathological levels of glutamate activity, memantine prevents damage caused by excitotoxicity but also permits the maintenance of physiological glutamate activity when given in lower doses.[25] It is most effective when more channels are open (which is maximized under pathological conditions of excess glutamate), which suggests that memantine is more effective at blocking the channels in cases of moderate or severe neurodegenerative disease severity rather than during milder stages.[30] Memantine has a shorter dwell time (or faster off-rate) than some of the earlier NMDA antagonists that were not tolerated, but a longer dwell time than Mg2+, which can be ineffective at blocking the channel. It has been shown to preferentially block extrasynaptic NMDA receptors over synaptic receptors in physiological conditions as well as in pathological conditions, when Mg2+ is repelled from the NMDA channel.[31] These factors make memantine a good candidate for the prevention of excessive glutamate activity.[25,29]
Chemistry, Pharmacodynamics & Pharmacokinetics
Memantine hydrochloride is a moderate-affinity uncompetitive NMDA receptor antagonist that is voltage-dependent and has fast on and off rates. The systematic International Union of Pure and Applied Chemistry name for memantine is 1-amino-3,5-dimethyladamantane hydrochloride; its molecular formula is C12H21N – HCl and molecular weight is 215.76.[32–34] Figure 1 depicts the chemical structure of memantine hydrochloride.
Figure 1.
Memantine hydrochloride.
Memantine is administered orally, and appears as a fine white-to-off-white powder that is soluble in water. Since 2002, it has been available as 5- and 10-mg tablets and as an oral solution for patients who have difficulty swallowing tablets. Dosing normally begins at 5 mg/day and is usually titrated to a final target dose of 20 mg/day, most often given in twice-daily doses of 10 mg.[34] Patients with severe renal impairment (creatinine clearance of 5–29 ml/min) are advised to limit their dose of memantine to 5 mg twice daily to avoid an excessive plasma concentration of memantine, since it is eliminated predominantly through renal mechanisms.[35]
In June 2010, the US FDA approved a new extended-release (ER) formulation of memantine (memantine ER), which provides a once-daily 28-mg dose of memantine.[102] Memantine ER is available as 7, 14, 21 and 28-mg capsules of ER beads, which contain the respective amounts of memantine hydrochloride. Dosing should begin at 7 mg/day, and increase weekly in 7-mg increments until reaching the final dose of 28 mg/day. If a patient is switching from 10 mg twice daily conventional memantine to memantine ER, the patient may transition to the 28-mg dose of memantine ER immediately instead of following the titration schedule. The medication can be taken without regards to food. Capsules should be consumed whole, if possible. For patients who have difficulty swallowing, the capsules may be opened so that the contents can be administered as a mixture in apple sauce. There are no suggested dose modifications for patients with hepatic impairment; however, general caution is advised for patients with severe hepatic impairment as memantine has not been formally studied in this patient population. Patients with mild or moderate renal impairment should keep the recommended 28 mg/day target dose, but patients with severe renal impairment (creatinine clearance of 5–29 ml/min) should reduce the maximum dose to 14 mg/day.[102]
Memantine ER is well absorbed, and reaches a maximum concentration at approximately 9–12 h postdose,[102] compared with approximately 3–7 h for conventional memantine.[34] Overall absorption of both memantine and memantine ER is not affected by food, however the time to peak absorption is shortened with food. The pharmacokinetic profile is approximately linear across therapeutic doses. Memantine ER at 28 mg once daily has been shown to reach a maximum concentration that is 48% higher and a 24-h area under the curve that is approximately 33% higher than 10 mg twice daily memantine. The elimination half-life of memantine is about 60–80 h.[102] The apparent clearance of memantine is affected by total bodyweight, type of memantine formulation (solution or tablets for conventional-release memantine), and concomitant medications that are eliminated by tubular secretion.[36] One steady-state pharmacokinetic study of memantine ER in healthy adults found the half-life of memantine ER to be slightly shorter, at 41–74 h.[37] Approximately 48% of memantine is excreted as unmetabolized memantine; the remainder is broken down to primarily three metabolites (N-glucuronide conjugate, 6-hydroxy memantine and 1-nitroso deaminated memantine), which are minimally active as NMDA receptor antagonists.[102]
Memantine selectively inhibits CYP2B6 enzymes, but is not expected to interact with the CYP450 enzymes.[38] It also does not affect the pharmacokinetics of donepezil or bupropion. Memantine's pharmacokinetic activity is not affected by bupropion, or by CYP450 substrates or inhibitors. Its proportion bound to plasma protein is low (45%); accordingly memantine is not expected to interact with warfarin or digoxin.[102] Memantine has been found to block nicotinic acetylcholine receptors at the cellular level,[39,40] but it is unclear whether this effect has any clinical relevance. Memantine also exerts antagonistic effects at the 5HT3 receptor[41] and enhances histaminergic receptor activity,[42] both of which could possibly contribute towards synergistic effects in cognitive enhancement.
Clinical Efficacy
Moderate-to-severe AD Three Phase III trials of 20 mg/day memantine in moderate-to-severe AD – MRZ9605,[43] MEM-MD-01[44] and MEM-MD-02[45] – were completed in the USA prior to the first approval of memantine for the treatment of moderate-to-severe AD. A total of over 1000 participants enrolled in the studies, 507 of which received memantine. Each of the AD trials were approximately 6 months in duration, and the memantine treatment group had a greater completion rate for all three trials. Memantine was tested as a monotherapy for AD in the MRZ9605 and MEM-MD-01 trials. The MEM-MD-02 study evaluated memantine as a combination therapy with concurrent donepezil treatment. Table 1 shows highlights of the baseline characteristics and eligibility criteria for each of these studies.
Memantine treatment was associated with statistically significantly improved outcomes on measures of cognition and function in the MRZ9605 and MEM-MD-02 trials, and additionally on measures of behavior and global assessment in the MEM-MD-02 trial (Table 1). Global outcomes also favored memantine in the MRZ9605 study, but this difference was not statistically significant.[43] Most of the benefit was experienced as less worsening in the memantine group compared with the placebo group; however, the MEM-MD-02 study also demonstrated that the memantine group's performance on the cognitive measure improved.[45–48] Potential impact on caregiver burden and burden to society were also evaluated in the MRZ9605 trial. These analyses revealed an association between memantine treatment and a reduction in caregiver time spent on caring for patients, delayed time to institutionalization, lower monthly caregiver costs and lower total societal costs.[49] Memantine's beneficial effect on time to institutionalization and total societal costs for moderate-to-severe Alzheimer's patients was further supported by two cost-effective analyses performed in Finland and the UK.[50,51] A 24-week open-label extension of the MRZ9605 study found that rates of decline remained significantly slower on measures of cognition, function and global assessment compared with the projected rate of decline of the placebo group from the double-blind study.[52]
None of the efficacy assessments in the MEM-MD-01 trial had significant separation between memantine and placebo at study end point, although the memantine group demonstrated an advantage on the cognitive assessment that was statistically significant at week 12. Post hoc analyses from the MEM-MD-01 study, which were performed to explore the effects of controlling for possible confounding variables and missing data, were also not significantly different. Analyses that adjusted for nonparametric distribution of scores on the efficacy assessments resulted in detection of a statistically significant difference favoring memantine on the cognitive assessment only. The reason that the outcomes of the MEM-MD-01 trial did not parallel the results of the MRZ9605 or MEM-MD-02 trials is unclear, especially given that the three studies used a similar protocol design. Differences in prior/concurrent use of a cholinesterase inhibitor, slight variation in duration of memantine treatment or subject demographics have been raised as possible reasons for the difference.[44]
To explore memantine's response specifically among patients who had one of several neuropsychiatric symptoms at baseline, Wilcock and colleagues performed a retrospective analysis of select subjects from the MEM-MD-01, MEM-MD-02 and MRZ9605 studies.[53] The researchers identified 593 subjects with baseline symptoms of agitation or psychosis, which was indicated by the presence of agitation/aggression, delusions, hallucinations, or any combination of those three items from the Neuropsychiatric Inventory (NPI). Of the subject pool of 593 participants, 287 were treated with placebo and 306 were treated with memantine. A total of 454 (76.6%) were reported as having agitation/aggression, 336 (56.7%) experiencing delusions and 172 (29.0%) experiencing hallucinations. Response to treatment was evaluated by assessing each of the three symptoms individually, and by grouping the symptoms together into one cluster, labeled agitation/psychosis. Memantine treatment was associated with significant benefits over placebo in the cluster of agitation/psychosis, and in the subsymptom of agitation/aggression. It was also numerically, but not statistically significantly, associated with benefits in the subitems of delusions and hallucinations. Memantine-treated patients also showed significantly less worsening in cognitive, global and functional outcomes, compared with placebo-treated patients. Patients who were free of any of the symptoms of agitation/psychosis at baseline had a lower rate of incidence of new symptoms in patients treated with memantine compared with patients treated with placebo.[53] The hypothesis that memantine provides a benefit specifically for patients who experience neuropsychiatric or behavioral symptoms is further supported by results from a larger pooled analysis of moderate-to-severe AD trials of memantine.[54]
Another earlier memantine trial – the Benefit and Efficacy in Severely Demented patients during Treatment with Memantine (M-Best or 9403) study – enrolled participants with moderately severe AD as well as patients with vascular dementia. This 12-week study enrolled 166 nursing home and psychiatric hospital patients aged 60–80 years who scored less than 10 on the Mini Mental State Examination (MMSE) (mean 6.3); 82 patients were randomized to memantine (10 mg/day) and 84 were randomized to placebo. Overall outcomes significantly favored the treatment group on measures of global assessment and care dependency, and a subanalysis of patients who met criteria for AD dementia showed that memantine-treated patients had a superior response on the global assessment compared with patients treated with placebo (73 vs 42%, respectively).[55]
Mild-to-moderate AD Memantine has also been evaluated for the treatment of mild-to-moderate AD, although overall results from these studies offer limited support for the use of memantine in milder stages of AD. One recent meta-analysis demonstrated the lack of support for memantine use in the earliest stages by assessing only patients who met criteria for mild AD (MMSE scores of 20–23) and finding no separation between memantine and placebo in any of the outcome measures.[56] Most published placebo-controlled trials of memantine in earlier AD, however, have not restricted enrollment to mild AD. Each of the three major early AD studies – MEM-MD-10, Study 99679 and MEM-MD-12 – assessed memantine 20 mg/day in patients at least 50 years of age with a diagnosis of mild-to-moderate AD (MMSE scores of 10–23), using the Alzheimer's Disease Assessment Scale – cognitive subscale (ADAS-cog) and Clinician's Interview-Based Impression of Change Plus Caregiver Input (CIBIC-plus) as primary efficacy end points and the NPI and 23-item Alzheimer Disease Cooperative Study Activities of Daily Living scale (ADCS-ADL-23) as secondary efficacy end points (Table 1). MEM-MD-10 was the first and most promising trial, testing memantine (10 mg twice daily) as a monotherapy for AD treatment in patients who had a baseline MMSE of 10–22. At the end of the 24-week treatment period, the ADAS-cog, CIBIC-plus and NPI showed statistically significant benefits favoring memantine treatment.[57] While analyzing the seperate components of the ADAS-cog, investigators found that benefits in language and memory, but not praxis, were affiliated with memantine treatment.[58] Study 99679 also evaluated memantine (10 mg twice daily) as a monotherapy in a similar patient population (MMSE of 11–23, inclusive). Although the 24-week scores in the ADAS-cog and CIBIC-plus numerically favored the use of memantine, the changes from baseline were not significantly different between the memantine and placebo treatment groups.[59] The MEM-MD-12 study, which evaluated memantine (20 mg once daily) in patients who had a baseline MMSE score of 10–22 and were taking a stable dose of cholinesterase inhibitor at baseline, showed no meaningful difference in any of the efficacy assessments.[60]
The MEM-MD-10 trial was followed by a 28-week extension that was used to evaluate not only the long-term safety and tolerability of memantine in patients with mild-to-moderate AD, but also to assess varying dosing regimens and titration schedules.[61] Patients who had previously been treated with placebo were assigned to one of two titration schedules: weekly dose increases by 5 mg increments over 4 weeks until reaching a final dose of 10 mg memantine given twice daily, or biweekly dose increases by 5 mg increments over 8 weeks until establishing a target dose of 20 mg memantine given once daily at night. The patients who were treated with memantine during the MEM-MD-10 trial were randomized to either continue the 10 mg twice-daily dosing, or switch to 20-mg memantine given as a single dose at night. Clinical efficacy assessments were administered at the end of the 28-week extension period, but results were not discussed by the study authors. The different titration schedule did not seem to influence discontinuation rates. Two adverse events (AEs) – somnolence and agitation – were more common in patients receiving 20-mg memantine as a single dose compared with patients receiving memantine as two doses of 10 mg.[61]
Potential changes in brain-imaging biomarkers associated with memantine in the treatment of mild-to-moderate AD have also been explored in the context of a pilot feasibility study.[62] Investigators assessed total and hippocampal brain volume, global and regional glucose utilization, regional N-acetylaspartate and regional myoinositol (chemical shift) from baseline to week 52 in a clinical trial of memantine monotherapy in 36 patients with mild-to-moderate AD (MMSE 14–22). At week 52, the total study population showed statistically significant reductions in total and hippocampal brain volume, and in global glucose metabolism. There were no statistically significantly different changes between the memantine and placebo group, however the placebo group showed numerically greater decline in glucose utilization and hippocampal volume.[62]
Memantine 20-mg Once Daily The long elimination half-life of memantine makes the medication a potential candidate for once-daily dosing. Within approximately 2 weeks of treatment the plasma concentration of memantine is expected to reach a steady state, and calculations suggest that the difference in peak-to-trough levels between 20-mg once-daily and 10-mg twice-daily dosing is small.[63] Data from the MEM-MD-12 trial and open-label extension of the MEM-MD-10 demonstrate that once-daily dosing is generally well tolerated in patients with mild-to-moderate AD.[60,61] One randomized trial of once-daily versus twice-daily dosing of memantine in patients with moderate-to-severe AD[64] as well as an open-label study of 20-mg memantine given once daily[65] have supported the favorable safety and tolerability profile for once-daily dosing in more advanced AD. Although the recommended dosing for conventional memantine is 10-mg twice daily, it may be feasible for some patients to take the full daily dose only once per day, which might improve medication compliance.
Memantine ER: 28-mg Formulation There has been one unpublished placebo-controlled study to test the safety and efficacy of the memantine ER 28-mg/day formulation (Box 1), but so far no studies to evaluate the ER formulation against the conventional 10 mg twice daily or 20 mg once daily dosing. The results from the placebo-controlled trial have not been fully published; however, findings have been reported at scientific meetings.[66] The multicenter international trial evaluated 24 weeks of treatment with memantine ER in addition to stable cholinesterase inhibitor treatment, following a 2-week placebo lead-in phase. Eligible participants were at least 50 years of age, and had scored 3–14 out of 30 on the baseline MMSE. A total of 676 participants were enrolled in the study; 335 were given placebo and 342 were treated with memantine. The mean MMSE score at baseline was 10.8 (10.6 in the placebo group, and 10.9 in the memantine group), and mean years of education was 8.9 ± 4.5 in the placebo group and 8.8 ± 4.5 in the memantine group. The completion rates were similar between groups, with 81.2% of participants from the placebo group and 79.8% in the memantine group. Dosing was initiated at 7 mg/day, and increased weekly by 7-mg increments until reaching the target dose of 28 mg/day at week 4. Primary efficacy outcomes were cognitive performance, as measured by the Severe Impairment Battery (SIB), and global assessment, which was evaluated by the CIBIC-plus.[67]
Statistically significant differences were found on both primary outcome measures at the end of study, based on the last observation carried forward and observed cases analyses. The memantine group had significant improvement on both the SIB and CIBIC-plus.[67] Specific areas of cognitive benefit included attention (as captured by several components of the SIB) and verbal fluency (as measured by the number of animals the patients could list in 1 min). Benefits in these areas were modest, but statistically significant at end point using the last observation carried forward, as well as at weeks 18 and 24 in the observed cases.[68] Behavioral and functional outcomes were also evaluated as secondary outcomes, using the NPI and ADCS-ADL-19 respectively. Compared to the placebo group, the memantine group experienced significantly greater improvement on the NPI at end point and at weeks 12 and 18. When considering the domains of the NPI individually, delusions, agitation/aggression, irritability/lability, and night-time behavior were found to have significant differences at week 24, all of which favored the memantine group.[69] No significant separation was detected by the ADL assessment.[67]
The possible effects of memantine ER on caregiver burden were also assessed, and a significant difference between the two groups was noted at end point. More caregivers of placebo-group members reported that their burden had increased since the start of the study, while memantine-group caregivers were more likely to report an experienced reduction in caregiver burden. Perceived caregiver burden strongly correlated with the participants' dementia severity, and reduced caregiver burden was associated with an increase in the amount of time caregivers spent in meaningful conversation with the patients.[70]
Postmarketing Surveillance
Conventional-release memantine has been followed in at least two longitudinal retrospective studies, both of which had positive responses associated with memantine use.[71,72] One of the studies, which followed patients from an AD research clinic in Pittsburgh Pennsylvania for 0.8–18 years per patient, explored the possible association that AD medication use has with institutionalization or mortality. Controlling for age, educational level, MMSE score at baseline, duration of AD symptoms, APOE4 allele and several medical comorbidities and concurrent medications, time to institutionalization was assessed comparing patients treated with memantine plus a cholinesterase inhibitor, patients treated with cholinesterase inhibitor only, and patients who were not taking any AD medications. Time to nursing home placement was significantly reduced in patients who were given cholinesterase inhibitors compared with patients who received no treatment, and this delay was even greater among patients who were treated with both cholinesterase inhibitor and memantine. Time to death was not associated with either of the medication regimens.[71]
The second study followed patients from a memory disorders clinic at Massachusetts General Hospital (MA, USA) to compare cognitive and functional outcomes between patients who received no pharmacological treatment, patients who were treated with cholinesterase inhibitor only, and patients who were given memantine in addition to a cholinesterase inhibitor. Patients were followed in the study for an average of 30 months. Treatment with memantine and cholinesterase inhibitor was associated with a slower rate of decline in cognitive and functional impairment compared with both the cholinesterase inhibitor-only group and the no treatment group. The cholinesterase inhibitor-only group had significant slowing in the change of cognitive outcomes, but no significant difference in functional outcomes.[72]
A new randomized controlled trial to compare the clinical- and cost-effectiveness of memantine monotherapy, donepezil monotherapy, or memantine plus donepezil combination therapy to treatment with placebo in patients with moderate-to-severe AD is currently underway in the UK. Researchers from the 15 centers are aiming to evaluate the benefit of the various treatment options specifically for patients who are transitioning from moderate AD to severe AD.[73] The trial finished recruiting participants in March 2008, and is scheduled to follow participants for 2 years in clinic and 5 years via telephone.[103]
Safety & Tolerability
In general, analyses of memantine's safety and tolerability profile have been favorable.[74] The most commonly reported AE experienced during placebo-controlled trials of conventional memantine include dizziness, headache, confusion and constipation.[34] Farlow and others completed a pooled safety analysis of 2311 patients enrolled in six randomized controlled trials (MRZ9605, MEM-MD-01, MEM-MD-02, MEM-MD-10, MEM-MD-12 and Study 99679).[75] Across all of the randomized controlled trials, memantine-treated participants were equally likely to experience at least one treatment-emergent AE as placebo-treated participants (57.2% memantine vs 57.9% placebo). Memantine-treated participants also had a similar rate of discontinuation due to any AE as placebo-treated participants (8.9% memantine vs 9.8% placebo). There were no statistically significant differences between memantine- and placebo-treated patients in proportion of death or serious AE, although the proportion of both deaths and serious AEs was numerically greater in half of the placebo-controlled trials. When considering the total pooled population, the proportion of deaths were equal and the proportion of serious AEs were greater among placebo-treated patients.[75]
Memantine is safe to use in addition to cholinesterase inhibitors for the treatment of dementia. One preclinical study with rats determined that memantine does not diminish the activity of donepezil or galantamine.[76] A pharmacokinetic study of one single dose of memantine added to concurrent donepezil treatment in healthy volunteers found no evidence of an interaction between memantine and donepezil.[77] Clinical trials[45,60] and a postmarketing study that have examined the combined treatment of memantine and cholinesterase inhibitors in patients with dementia also found promising safety and tolerability outcomes.
There has been one trial to assess the safety and tolerability of the ER formulation of memantine specifically.[102] A total of 676 participants (341 treated with memantine ER and 335 with placebo) composed the safety population of this 24-week placebo-controlled study. The discontinuation rate was higher in the memantine ER group (10%) compared with the placebo group (6.3%). Dizziness was the most common AE that led to discontinuation from the study. The most frequently observed AEs (Table 2) that were greater in the memantine ER group than in the placebo group were headache (6 vs 5%), dizziness (5 vs 1%), diarrhea (5 vs 4%), hypertension (4 vs 2%), anxiety (4 vs 3%) and influenza (4 vs 3%).[102] Each of these AEs, except for diarrhea and anxiety, were also experienced more frequently by memantine-treated participants from the pooled safety analysis.[75] There were no significant changes in vital signs, laboratory test parameters or electrocardiogram parameters for all formulations.[102]
Regulatory Affairs
Memantine was first patented by Merz Pharmaceuticals (Germany), and was later licensed to Forest Laboratories in the USA and Lundbeck (Denmark) for several other international markets.[104] Trade names for memantine include Axura® (Merz Pharmaceuticals GmbH), Ebixa® (H Lundbeck A/S) and Namenda (Forest Laboratories, Inc.).[105,106] Ebixa was first authorized for the treatment of moderate-to-severe AD by the EMA on 15 May, 2002, and was closely followed by the EMA's authorization of Axura on 17 May, 2002.[105]
In the USA, Namenda was first approved for the treatment of moderate-to-severe AD on 16 October 2003, and the patent held by Forest Laboratories, Inc. is scheduled to expire in April 2015. Presently six additional pharmaceutical companies have received tentative approval from the FDA for generic formulations of memantine hydrochloride, but none of these agents are available in the market yet. Namenda XR was approved by the FDA on 21 June 2010.[106] Generic formulations of conventional-release memantine were also approved by Health Canada in late 2009 and early 2010. Currently in Canada, memantine is available as Ebixa (Lundbeck Canada Inc., Montreal, QC, Canada), which was approved in December 2004.[107]
Memantine is marketed by Lundbeck in the UK, also under the trade name Ebixa. Following a more recent clinical efficacy and cost-effectiveness analysis from the NICE, new guidelines suggest that patients with moderate AD who cannot tolerate a cholinesterase inhibitor, as well as patients with severe AD (MMSE <10), may be treated with memantine under the care of a dementia specialist. NICE still does not recommend memantine for the treatment of mild AD.[108]
Aging Health. 2011;7(3):349-362. © 2011 Future Medicine Ltd.
Cite this: Memantine: A Treatment for Alzheimer's Disease With a New Formulation - Medscape - Jun 01, 2011.
