A1,
A2,
B,
C1,
C2,
D,
E,
F,
G-H,
I-K,
L,
M,
N,
O,
P1,
P2,
Q-R,
S,
T,
U-V,
W-Z
Namenda Pharmacology, Pharmacokinetics, Studies, Metabolism - Memantine
Namenda Pharmacology, Pharmacokinetics, Studies, Metabolism - Memantine
CLINICAL PHARMACOLOGY
Mechanism of Action and Pharmacodynamics
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.
Pharmacokinetics
Memantine is well absorbed after oral administration and has
linear pharmacokinetics over the therapeutic dose range. It is excreted predominantly
in the urine, unchanged, and has a terminal elimination half life of about 60-80
hours.
Absorption and Distribution
Following oral administration memantine is highly absorbed
with peak concentrations reached in about 3-7 hours. Food has no effect on the
absorption of memantine. The mean volume of distribution of memantine is 9-11
L/kg and the plasma protein binding is low (45%).
Metabolism and Elimination
Memantine undergoes little metabolism, with the majority (57-82%)
of an administered dose excreted unchanged in urine; the remainder is converted
primarily to three polar metabolites: the N-gludantan conjugate, 6-hydroxy memantine,
and 1-nitroso-deaminated memantine. These metabolites possess minimal NMDA receptor
antagonist activity. The hepatic microsomal CYP450 enzyme system does not play
a significant role in the metabolism of memantine. Memantine has a terminal
elimination half-life of about 60-80 hours. Renal clearance involves active
tubular secretion moderated by pH dependent tubular reabsorption.
Special Populations
Renal Impairment: Adequate information on the effect
of renal impairment on the pharmacokinetics of memantine is not available. As
the major route of elimination is renal, however, it is very likely that subjects
with moderate and severe renal impairment will have significantly higher exposure
than normal subjects.
Elderly: The pharmacokinetics of NAMENDA in young and
elderly subjects are similar.
Gender: Following multiple dose administration of NAMENDA
20 mg b.i.d, females had about 45 % higher exposure than males,but there
was no difference in exposure when body weight was taken into account..
Drug-Drug Interactions
Substrates of Microsomal Enzymes: In-vitro studies have
shown that memantine produces minimal inhibition of CYP450 enzymes CYP1A2, CYP2A6,
CYP2C9, CYP2D6, CYP2E1, and CYP3A4. These data indicate that no pharmacokinetic
interactions with drugs metabolized by these enzymes are expected.
Inhibitors of Microsomal Enzymes: Since memantine undergoes
minimal metabolism,with the majority of the dose excreted unchanged in urine,
an interaction between memantine and drugs that are inhibitors of CYP 450 enzymes
is unlikely.Co-administration of NAMENDA with the AChE inhibitor donepezil
HCl does not affect the pharmacokinetics of either compound.
Drugs Eliminated via Renal Mechanisms: Memantine is
eliminated in part by tubular secretion. In-vivo studies have shown that
multiple doses of the diuretic hydrochlorothiazide/triamterene (HCTZ/TA) did
not affect the AUC of memantine at steady state. Memantine did not affect the
bioavailability of TA, and decreased AUC and Cmax of HCTZ by about
20%.
Drugs that make the urine alkaline: The clearance of
memantine was reduced by about 80% under alkaline urine conditions at pH 8.
Therefore, alterations of urine pH towards the alkaline state may lead to an
accumulation of the drug with a possible increase in adverse effects. Drugs
that alkalinize the urine (e.g. carbonic anhydrase inhibitors, sodium bicarbonate)
would be expected to reduce renal elimination of memantine.
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.
CLINICAL TRIALS
The effectiveness of NAMENDA (memantine hydrochloride) as a
treatment for patients with moderate to severe Alzheimer’s disease was demonstrated
in 2 randomized, double-blind, placebo-controlled clinical studies (Studies
1 and 2) conducted in the United States that assessed both cognitive function
and day to day function. The mean age of patients participating in these two
trials was 76 with a range of 50-93 years. Approximately 66% of patients were
female and 91% of patients were Caucasian.
A third study (Study 3), carried out in Latvia, enrolled patients
with severe dementia, but did not assess cognitive function as a planned endpoint.
Study Outcome Measures: In each U.S. study, the effectiveness
of NAMENDA was determined using both an instrument designed to evaluate overall
function through caregiver-related assessment, and an instrument that measures
cognition. Both studies showed that patients on NAMENDA experienced significant
improvement on both measures compared to placebo.
Day-to-day function was assessed in both studies using the
modified Alzheimer’s disease Cooperative Study – Activities of Daily Living
inventory (ADCS-ADL). The ADCS-ADL consists of a comprehensive battery of ADL
questions used to measure the functional capabilities of patients. Each ADL
item is rated from the highest level of independent performance to complete
loss. The investigator performs the inventory by interviewing a caregiver familiar
with the behavior of the patient. A subset of 19 items, including ratings of
the patients’ ability to eat, dress, bathe, telephone, travel, shop, and perform
other household chores has been validated for the assessment of patients with
moderate to severe dementia. This is the modified ADCS-ADL, which has a scoring
range of 0 to 54, with the lower scores indicating greater functional impairment.
The ability of NAMENDA to improve cognitive performance was
assessed in both studies 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
cognitive impairment.
Study 1 (Twenty-Eight-Week Study)
In a study of 28 weeks duration, 252 patients with moderate
to severe probable Alzheimer’s disease (diagnosed by DSM-IV and NINCDS-ADRDA
criteria, with Mini-Mental State Examination scores =3 and =14 and Global Deterioration
Scale Stages 5-6) were randomized to NAMENDA or placebo. For patients randomized
to NAMENDA, treatment was initiated at 5 mg once daily and increased weekly
by 5 mg/day in divided doses to a dose of 20 mg/day (10 mg twice a day).
Effects on the ADCS-ADL:
At 28 weeks of treatment, the mean difference in the ADCS-ADL
change scores for the NAMENDA -treated patients compared to the patients on
placebo was 3.4 units. Using an analysis based on all patients and carrying
their last study observation forward (LOCF analysis), NAMENDA treatment was
statistically significantly superior to placebo.
Both patients assigned to NAMENDA and placebo have a wide range
of responses and generally show deterioration (a negative change in ADCS-ADL
compared to baseline), but that the NAMENDA group is more likely to show a smaller
decline or an improvement. (In a cumulative distribution display, a curve for
an effective treatment would be shifted to the left of the curve for placebo,
while an ineffective or deleterious treatment would be superimposed upon or
shifted to the right of the curve for placebo.)
Effects on the SIB:
At 28 weeks of treatment, the mean difference in the SIB change
scores for the NAMENDA-treated patients compared to the patients on placebo
was 5.7 units. Using an LOCF analysis, NAMENDA treatment was statistically significantly
superior to placebo.
Both patients assigned to NAMENDA and placebo have a wide range
of responses and generally show deterioration, but that the NAMENDA group is
more likely to show a smaller decline or an improvement.
Study 2 (Twenty-Four-Week Study)
In a study of 24 weeks duration, 404 patients with moderate
to severe probable Alzheimer’s disease (diagnosed by NINCDS-ADRDA criteria,
with Mini-Mental State Examination scores =5 and =14) who had been treated with
donepezil for at least 6 months and who had been on a stable dose of donepezil
for the last 3 months were randomized to NAMENDA or placebo while still receiving
donepezil. For patients randomized to NAMENDA, treatment was initiated at 5
mg once daily and increased weekly by 5 mg/day in divided doses to a dose of
20 mg/day (10 mg twice a day).
Effects on the ADCS-ADL:
At 24 weeks of treatment, the mean difference in the ADCS-ADL
change scores for the NAMENDA/donepezil treated patients (combination therapy)
compared to the patients on placebo/donepezil (monotherapy) was 1.6 units. Using
an LOCF analysis, NAMENDA/donepezil treatment was statistically significantly
superior to placebo/donepezil.
Both patients assigned to NAMENDA/donepezil and placebo/donepezil
have a wide range of responses and generally show deterioration, but that the
NAMENDA/donepezil group is more likely to show a smaller decline or an improvement
Effects on the SIB:
At 24 weeks of treatment, the mean difference in the SIB change
scores for the NAMENDA/donepezil treated patients compared to the patients on
placebo/donepezil was 3.3 units. Using an LOCF analysis, NAMENDA/donepezil treatment
was statistically significantly superior to placebo/donepezil.
Both patients assigned to NAMENDA/donepezil and placebo/donepezil
have a wide range of responses, but that the NAMENDA/donepezil group is more
likely to show an improvement or a smaller decline.
Study 3 (Twelve-Week Study)
In a double-blind study of 12 weeks duration, conducted in
nursing homes in Latvia, 166 patients with dementia according to DSM- -R, a
Mini-Mental Status Examination score of < 10, and Global Deterioration Scale
staging of 5 to 7 were randomized to either NAMENDA or placebo. For patients
randomized to NAMENDA, treatment was initiated at 5 mg once daily and increased
to 10 mg once daily after 1 week. The primary efficacy measures were the care
dependency subscale of the Behavioral Rating Scale for Geriatric Patients (BGP),
a measure of day-to-day function, and a Clinical Global Impression of Change
(CGI-C), a measure of overall clinical effect. No valid measure of cognitive
function was used in this study. A statistically significant treatment difference
at 12 weeks that favored NAMENDA over placebo was seen on both primary efficacy
measures. Because the patients entered were a mixture of Alzheimer’s disease
and vascular dementia, an attempt was made to distinguish the two groups and
all patients were later designated as having either vascular dementia or Alzheimer’s
disease, based on their scores on the Hachinski Ischemic Scale at study entry.
Only about 50% of the patients had computerized tomography of the brain. For
the subset designated as having Alzheimer’s disease, a statistically significant
treatment effect favoring NAMENDA over placebo at 12 weeks was seen on both
the BGP and CGI-C.
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