Mechanism Of Action
Persistent activation of central nervous system
N-methyl-D-aspartate (NMDA) receptors by the excitatory amino acid glutamate
has been hypothesized to contribute to the symptomatology of Alzheimer's
disease. Memantine is postulated to exert its therapeutic effect through its
action as a low to moderate affinity uncompetitive (open-channel) NMDA receptor
antagonist which binds preferentially to the NMDA receptor-operated cation
channels. There is no evidence that memantine prevents or slows neurodegeneration
in patients with Alzheimer's disease.
Memantine showed low to negligible affinity for GABA,
benzodiazepine, dopamine, adrenergic, histamine and glycine receptors and for
voltage-dependent Ca2+, Na+, or K+ channels. Memantine
also showed antagonistic effects at the 5HT3 receptor with a potency similar to
that for the NMDA receptor and blocked nicotinic acetylcholine receptors with
one-sixth to one-tenth the potency.
In vitro studies have shown that memantine does not
affect the reversible inhibition of acetylcholinesterase by donepezil,
galantamine, or tacrine.
Memantine is well absorbed after oral administration and
has linear pharmacokinetics over the therapeutic dose range. It is excreted
predominantly unchanged in urine and has a terminal elimination half-life of
about 60-80 hours. In a study comparing 28 mg once daily NAMENDA XR to 10 mg
twice daily NAMENDA, the Cmax and AUC0-24 values were 48% and 33% higher for
the XR dosage regimen, respectively.
After multiple dose administration of NAMENDA XR,
memantine peak concentrations occur around 9-12 hours post-dose. There is no
difference in the absorption of NAMENDA XR when the capsule is taken intact or
when the contents are sprinkled on applesauce.
There is no difference in memantine exposure, based on Cmax
or AUC, for NAMENDA XR whether that drug product is administered with food or
on an empty stomach. However, peak plasma concentrations are achieved about 18
hours after administration with food versus approximately 25 hours after
administration on an empty stomach.
The mean volume of distribution of memantine is 9-11 L/kg
and the plasma protein binding is low (45%).
Memantine undergoes partial hepatic metabolism. The
hepatic microsomal CYP450 enzyme system does not play a significant role in the
metabolism of memantine.
Memantine is excreted predominantly in the urine,
unchanged, and has a terminal elimination half-life of about 60-80 hours. About
48% of administered drug is excreted unchanged in urine; the remainder is
converted primarily to three polar metabolites which possess minimal NMDA
receptor antagonistic activity: the N-glucuronide conjugate, 6hydroxy memantine,
and 1-nitroso-deaminated memantine. A total of 74% of the administered dose is
excreted as the sum of the parent drug and the N-glucuronide conjugate. Renal
clearance involves active tubular secretion moderated by pH dependent tubular
The pharmacokinetics of memantine in young and elderly
subjects are similar.
Following multiple dose administration of memantine HCl
20 mg daily, females had about 45% higher exposure than males, but there was no
difference in exposure when body weight was taken into account.
Memantine pharmacokinetics were evaluated following
single oral administration of 20 mg memantine HCl in 8 subjects with mild renal
impairment (creatinine clearance, CLcr, > 50 – 80 mL/min), 8 subjects with
moderate renal impairment (CLcr 30 – 49 mL/min), 7 subjects with severe renal
impairment (CLcr 5 – 29 mL/min) and 8 healthy subjects (CLcr > 80 mL/min)
matched as closely as possible by age, weight and gender to the subjects with
renal impairment. Mean AUC0-∞ increased by 4%, 60%, and 115% in subjects
with mild, moderate, and severe renal impairment, respectively, compared to
healthy subjects. The terminal elimination half-life increased by 18%, 41%, and
95% in subjects with mild, moderate, and severe renal impairment, respectively,
compared to healthy subjects.
Memantine pharmacokinetics were evaluated following the
administration of single oral doses of 20 mg in 8 subjects with moderate
hepatic impairment (Child-Pugh Class B, score 7-9) and 8 subjects who were
age-, gender-, and weight-matched to the hepaticallyimpaired subjects. There
was no change in memantine exposure (based on Cmax and AUC) in subjects with
moderate hepatic impairment as compared with healthy subjects. However,
terminal elimination half-life increased by about 16% in subjects with moderate
hepatic impairment as compared with healthy subjects.
Use with Cholinesterase Inhibitors
Coadministration of memantine with the AChE inhibitor
donepezil HCl did not affect the pharmacokinetics of either compound.
Furthermore, memantine did not affect AChE inhibition by donepezil. In a
24-week controlled clinical study in patients with moderate to severe
Alzheimer's disease, the adverse reaction profile observed with a combination
of memantine immediate-release and donepezil was similar to that of donepezil
Effect of Memantine on the Metabolism of Other Drugs
In vitro studies conducted with marker substrates of
CYP450 enzymes (CYP1A2, -2A6, 2C9, -2D6, -2E1, -3A4) showed minimal inhibition
of these enzymes by memantine. In addition, in vitro studies indicate that at
concentrations exceeding those associated with efficacy, memantine does not induce
the cytochrome P450 isozymes CYP1A2, -2C9, 2E1 and -3A4/5. No pharmacokinetic
interactions with drugs metabolized by these enzymes are expected.
Pharmacokinetic studies evaluated the potential of
memantine for interaction with warfarin and bupropion. Memantine did not affect
the pharmacokinetics of the CYP2B6 substrate bupropion or its metabolite
hydroxybupropion. Furthermore, memantine did not affect the pharmacokinetics or
pharmacodynamics of warfarin as assessed by the prothrombin INR.
Effect of Other Drugs on Memantine
Memantine is predominantly renally eliminated, and drugs
that are substrates and/or inhibitors of the CYP450 system are not expected to
alter the metabolism of memantine.
Drugs Eliminated via Renal Mechanisms
Because memantine is eliminated in part by tubular
secretion, coadministration of drugs that use the same renal cationic system,
including hydrochlorothiazide (HCTZ), triamterene (TA), metformin, cimetidine,
ranitidine, quinidine, and nicotine, could potentially result in altered plasma
levels of both agents. However, coadministration of memantine and HCTZ/TA did
not affect the bioavailability of either memantine or TA, and the
bioavailability of HCTZ decreased by 20%. In addition, coadministration of
memantine with the antihyperglycemic drug Glucovance (glyburide and metformin
HCl) did not affect the pharmacokinetics of memantine, metformin and glyburide.
Furthermore, memantine did not modify the serum glucose lowering effect of Glucovance,
indicating the absence of a pharmacodynamic interaction.
Drugs Highly Bound to Plasma Proteins
Because the plasma protein binding of memantine is low
(45%), an interaction with drugs that are highly bound to plasma proteins, such
as warfarin and digoxin, is unlikely.
Animal Toxicology And /Or Pharmacology
Memantine induced neuronal lesions (vacuolation and
necrosis) in the multipolar and pyramidal cells in cortical layers III and IV
of the posterior cingulate and retrosplenial neocortices in rats, similar to
those which are known to occur in rodents administered other NMDA receptor
antagonists. Lesions were seen after a single dose of memantine. In a study in
which rats were given daily oral doses of memantine for 14 days, the no-effect
dose for neuronal necrosis was 4 times the maximum recommended human dose (MRHD
of 28 mg/day) on a mg/m² basis.
In acute and repeat-dose neurotoxicity studies in female
rats, oral administration of memantine and donepezil in combination resulted in
increased incidence, severity, and distribution of neurodegeneration compared
with memantine alone. The no-effect levels of the combination were associated
with clinically relevant plasma memantine and donepezil exposures.
The relevance of these findings to humans is unknown.
The effectiveness of NAMENDA XR as a treatment for
patients with moderate to severe Alzheimer's disease was based on the results
of a double-blind, placebo-controlled trial.
24-week Study of NAMENDA XR Capsules
This was a randomized double-blind clinical investigation
in outpatients with moderate to severe Alzheimer's disease (diagnosed by DSM-IV
criteria and NINCDS-ADRDA criteria for AD with a Mini Mental State Examination
(MMSE) score ≥ 3 and ≤ 14 at
Screening and Baseline) receiving acetylcholinesterase
inhibitor (AChEI) therapy at a stable dose for 3 months prior to screening. The
mean age of patients participating in this trial was 76.5 years with a range of
49-97 years. Approximately 72% of patients were female and 94% were Caucasian.
Study Outcome Measures
The effectiveness of NAMENDA XR was evaluated in this
study using the co-primary efficacy parameters of Severe Impairment Battery
(SIB) and the Clinician's Interview-Based Impression of Change (CIBIC-Plus).
The ability of NAMENDA XR to improve cognitive
performance was assessed with the Severe Impairment Battery (SIB), a multi-item
instrument that has been validated for the evaluation of cognitive function in
patients with moderate to severe dementia. The SIB examines selected aspects of
cognitive performance, including elements of attention, orientation, language,
memory, visuospatial ability, construction, praxis, and social interaction. The
SIB scoring range is from 0 to 100, with lower scores indicating greater
The ability of NAMENDA XR to produce an overall clinical
effect was assessed using a Clinician's Interview Based Impression of Change
that required the use of caregiver information, the CIBIC-Plus. The CIBIC-Plus
is not a single instrument and is not a standardized instrument like the
ADCS-ADL or SIB. Clinical trials for investigational drugs have used a variety
of CIBIC formats, each different in terms of depth and structure. As such,
results from a CIBIC-Plus reflect clinical experience from the trial or trials
in which it was used and cannot be compared directly with the results of
CIBIC-Plus evaluations from other clinical trials. The CIBIC-Plus used in this
trial was a structured instrument based on a comprehensive evaluation at
baseline and subsequent time-points of four domains: general (overall clinical
status), functional (including activities of daily living), cognitive, and
behavioral. It represents the assessment of a skilled clinician using validated
scales based on his/her observation during an interview with the patient, in
combination with information supplied by a caregiver familiar with the behavior
of the patient over the interval rated. The CIBIC-Plus is scored as a seven
point categorical rating, ranging from a score of 1, indicating “marked
improvement” to a score of 4, indicating “no change” to a score of 7,
indicating “marked worsening.” The CIBIC-Plus has not been systematically
compared directly to assessments not using information from caregivers (CIBIC)
or other global methods.
In this study, 677 patients were randomized to one of the
following 2 treatments: NAMENDA XR 28 mg/day or placebo while still receiving
an AChEI (either donepezil, galantamine, or rivastigmine).
Effects on Severe Impairment Battery (SIB)
Figure 1 shows the time course for the change from
baseline in SIB score for the two treatment groups completing the 24 weeks of
the study. At 24 weeks of treatment, the mean difference in the SIB change
scores for the NAMENDA XR 28 mg/AChEI-treated (combination therapy) patients
compared to the patients on placebo/AChEI (monotherapy) was 2.6 units. Using an
LOCF analysis, NAMENDA XR 28 mg/AChEI treatment was statistically significantly
superior to placebo/AChEI.
Figure 1: Time course of the
change from baseline in SIB score for patients completing 24 weeks of
Figure 2 shows the cumulative
percentages of patients from each treatment group who had attained at least the
measure of improvement in SIB score shown on the X axis. The curves show that
both patients assigned to NAMENDA XR 28 mg/AChEI and placebo/AChEI have a wide
range of responses, but that the NAMENDA XR 28 mg/AChEI group is more likely to
show an improvement or a smaller decline.
Figure 2: Cumulative
percentage of patients completing 24 weeks of double-blind treatment with
specified changes from baseline in SIB scores.
Figure 3 shows the time course
for the CIBIC-Plus score for patients in the two treatment groups completing
the 24 weeks of the study. At 24 weeks of treatment, the mean difference in the
CIBIC-Plus scores for the NAMENDA XR 28 mg/AChEI-treated patients compared to
the patients on placebo/AChEI was 0.3 units. Using an LOCF analysis, NAMENDA XR
28 mg/AChEI treatment was statistically significantly superior to
Figure 3: Time course of the
CIBIC-Plus score for patients completing 24 weeks of treatment.
Figure 4 is a histogram of the
percentage distribution of CIBIC-Plus scores attained by patients assigned to
each of the treatment groups who completed 24 weeks of treatment.
Figure 4: Distribution of
CIBIC-Plus ratings at week 24.