mechanism of action
constant activation ofCentral Nervous SystemN-methyl-D-aspartate (NMDA) receptors by the excitatoryamino acids glutamateIt has been thought to contribute to the symptomatology ofAlzheimer disease. Memantine is postulated to exert its therapeutic effect through its mild to moderate effects.affinitynon-competitive NMDA receptor (open channel)AdversaryIt preferentially binds to cation channels activated by the NMDA receptor. There is no evidence that memantine prevents or delays neurodegeneration in patients with Alzheimer's disease.
Memantine showed negligible and low affinity for GABA, benzodiazepines,dopamine, adrenergic,histamineYwisteriareceptors and for voltage-gated Ca2+, Na+, or K+ channels. Memantine also showed antagonistic effects at the 5HT3 receptor with a potency similar to that of the NMDA receptor and blocked nicotine.acetylcholineReceivers with one sixth to one tenth of the power.
In vitro studies have shown that memantine does not affect the reversible inhibition ofacetilcolinesterasaB. by donepezil, galantamine, or tacrine.
After oral administration, memantine is extensively absorbed, with peak concentrations reached after approximately 3 to 7 hours. Memantine has linear pharmacokinetics in the therapeutic dose range. Food does not affect the absorption of memantine.
The mean volume of distribution of memantine is 9-11 L/kg and plasma protein binding is low (45%).
Memantine is partly treated via the liver.metabolism. The CYP450 hepatic microsomal enzyme system does not play an important role in the metabolism of memantine.
Memantine is excreted predominantly (about 48%) unchanged in the urine and has a terminal elimination half-life of about 60 to 80 hours.
The remainder is primarily converted to three polar metabolites that have minimal NMDA receptor antagonist activity: the N-glucuronide conjugate, 6-hydroxymemantine, and 1-nitroso-deaminated memantine. A total of 74% of the administered dose is excreted as the sum of the parent compound and the nglucuronide conjugate. Renal clearance involves active tubular secretion moderated by pH-dependent tubular reabsorption.
Pharmacokinetics in Specific Populations
Following multiple daily 20 mg doses of NAMENDA, women had approximately 45% higher exposure than men, but there was no difference in exposure when body weight was taken into account.
The pharmacokinetics of NAMENDA in young and elderly patients is similar.
Memantine pharmacokinetics following a single 20 mg oral dose of memantine hydrochloride were studied in 8 patients with mild renal impairment (creatinine clearance, CLcr > 50-80 mL/min), 8 patients with moderate renal impairment (CLcr 30 -49ml/min). min) and 7 evaluated patients with severe renal insufficiency (CLcr 5-29 mL/min) and 8 healthy subjects (CLcr > 80 mL/min) who matched the subjects with renal insufficiency as closely as possible for age, weight, and sex. The mean AUC0-∞ was 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 was prolonged by 18%, 41%, and 95% in subjects with mild, moderate, and severe renal impairment, respectively, compared to healthy subjects.
No dose adjustment is recommended in patients with mild or moderate renal impairment. The dose should be reduced in patients with severe renal insufficiency [seeDOSE AND APPLICATION].
The pharmacokinetics of memantine were evaluated after administration of a single 20 mg oral dose in 8 subjects with moderate hepatic impairment (Child-Pugh class B, score 7-9) and 8 subjects whose age, sex, and weight matched those of the subjects. with liver failure. There was no change in memantine exposure (based on Cmax and AUC) in subjects with moderate hepatic impairment compared to healthy subjects. However, the terminal elimination half-life was increased by approximately 16% in subjects with moderate hepatic impairment compared to healthy subjects. No dose adjustment is recommended in patients with mild or moderate hepatic impairment. Memantine should be administered with caution to patients with severe hepatic impairment as the pharmacokinetics of memantine in this patient population have not been studied.
Use with cholinesterase inhibitors
Simultaneous administration of memantine with theeffortsThe 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 NAMENDA and donepezil was similar to that of donepezil alone.
Effect of NAMENDA on the metabolism of other drugs
In vitro studies performed with marker substrates of CYP450 enzymes (CYP1A2, -2A6, -2C9, -2D6, 2E1, -3A4) showed minimal inhibition of these enzymes by memantine. Besides,in vitroStudies indicate that memantine does not induce cytochrome P450 isoenzymes CYP1A2, -2C9, -2E1, and -3A4/5 at concentrations greater than those associated with efficacy. Pharmacokinetic interactions with drugs metabolized by these enzymes are not expected.
Pharmacokinetic studies evaluated the potential for interaction of memantine with warfarin and bupropion. Memantine did not affect the pharmacokinetics of bupropion, a CYP2B6 substrate, or its metabolite, hydroxybupropion. In addition, memantine had no effect on the pharmacokinetics or pharmacodynamics of warfarin as assessed by theProthrombinINR.
Effect of other drugs on NAMENDA
Memantine is primarily excreted via the kidneys and medicinal products that are substrates and/or inhibitors of the CYP450 system are not expected to alter memantine metabolism.
Drugs excreted by the kidneys.
Because memantine is partially eliminated by tubular secretion, co-administration with drugs that use the same renal cation system, including hydrochlorothiazide (HCTZ), triamterene (TA), metformin, cimetidine, ranitidine, and quinidineNicotine, could lead to altered plasma levels of both active ingredients. However, co-administration of NAMENDA and HCTZ/TA did not affect the bioavailability of memantine or TA, and HCTZ bioavailability was decreased by 20%. In addition, co-administration of memantine with the antihyperglycemic drug Glucovance® (glyburide and metformin HCl) had no effect on the pharmacokinetics of memantine, metformin, and glyburide. Furthermore, memantine did not alter the hypoglycemic effect of Glucovance®, indicating a lack of pharmacodynamic interaction.
Drugs that are highly bound to plasma proteins
Since 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 andNecrosis) in multipolar and pyramidal cells incorticalLayers III and IV of therearcingulate and retrosplenial neocortex in rats similar to those known to occur in rodents given other NMDA receptor antagonists. Lesions were observed after a single dose of memantine. In a study in which rats were administered daily oral doses of memantine for 14 days, the no-effect dose for neuronal necrosis was 6 times the maximum recommended human dose of 20 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 an increased incidence, severity, and distribution of neurodegeneration compared with memantine alone. No-effect levels of the combination were associated with clinically relevant plasma exposures to memantine and donepezil.
The relevance of these findings to humans is unknown.
The clinical efficacy studies described below were performed with NAMENDA tablets and not with NAMENDA oral solution; However, the bioequivalence of NAMENDA oral solution with NAMENDA tablets has been demonstrated.
The efficacy of NAMENDA in the treatment of patients with moderate to severe Alzheimer's disease was demonstrated in two randomized, double-blind, placebo-controlled clinical trials (Trials 1 and 2) conducted in the United States, evaluatingcognitivefunction and everyday function. The mean age of the patients who participated in these two studies was 76 years, with a range of 50 to 93 years. Approximately 66% of the patients were female and 91% of the patients were Caucasian. A third study (Study 3) conducted in Latvia included patients withdementia, but did not assess cognitive functioning as the planned endpoint. Study Outcome Measures: In each US study, the efficacy of NAMENDA was assessed using an instrument to assess general functioning through the nursing-related assessment and a measurement instrumentComprehension. Both studies showed that patients on NAMENDA experienced a significant improvement on both measures compared to placebo.
Daily functioning was assessed in both studies using the Modified Cooperative Study of Alzheimer's Disease:daily life activitiesInventory (ADCS-ADL). The ADCS-ADL is a comprehensive set of ADL questions used to measure a patient's functional capacity. Each ADL item is graded from the highest level of independent performance to total loss. The investigator conducts the inventory by interviewing a nurse who is familiar with the patient's behavior. A subset of 19 items, including ratings of the patient's ability to eat, dress, bathe, use the telephone, travel, shop, and perform other household tasks, were validated for the assessment of patients with moderate to severe dementia. This is the modified ADCS-ADL, which has a score range of 0 to 54, with lower scores indicating greater functional impairment.
The ability of NAMENDA to improve cognitive performance was assessed in both studies using the Severe Impairment Battery (SIB), a multi-item instrument that has been validated to assess cognitive function in patients with moderate to severe dementia. The SIB examines selected aspects of cognitive performance, including items of attention, orientation, language, memory, visuospatial ability, construction, practice, and social interaction. The SIB score ranges from 0 to 100, with lower scores indicating greater cognitive decline.
Study 1 (28 week study)
In a 28-week study, 252 patients with probable moderate to severe Alzheimer's disease (diagnosed byDSM-IVand NINCDS-ADRDA criteria, with Mini-Mental State Examination Scores ≥3 and ≤14 and Global Impairment Scale stages 5-6) were randomized to NAMENDA or placebo. In patients randomized to NAMENDA, treatment was initiated with 5 mg once daily and increased weekly by 5 mg/day in divided doses up to a dose of 20 mg/day (10 mg twice daily).
Impact on ADL of ADCS
Figure 1 shows the time course of change from baseline in ADCS-ADL score for patients in the two treatment groups who completed the 28-week study. After 28 weeks of treatment, the mean difference in ADCS-ADL change scores for NAMENDA-treated patients compared to placebo-treated patients was 3.4 units. Using an analysis based on all patients and continuing with the last observation in the study (LOCF analysis), treatment with NAMENDA was statistically significantly superior to placebo.
Figure 1: Time course of change from baseline in ADCS-ADL score for patients who completed 28 weeks of treatment.
Figure 2 shows the cumulative percentage of patients in each of the treatment groups who achieved at least the change in ADCS-ADL indicated in the Xaxis. The curves show that both patients assigned to NAMENDA and placebo have a wide range of responses and generally worsen (a negative change in ADCS-ADL compared to baseline), but that the NAMENDA group tends to have less deterioration. or response improvement. (In a cumulative distribution screen, an effective treatment curve would shift to the left of the placebo curve, while an ineffective or harmful treatment would overlap or shift to the right of the placebo curve.)
Figure 2: Cumulative percentage of patients completing 28 weeks of double-blind treatment with specific changes from baseline in ADCS-ADL scores.
Effects on the SIB
Figure 3 shows the time course of change in SIB score from baseline for the two treatment groups over the 28 weeks of the study. After 28 weeks of treatment, the mean difference in SIBchange scores for NAMENDA-treated patients compared to placebo-treated patients was 5.7 units. Based on a LOCF analysis, treatment with NAMENDA was statistically significantly superior to placebo.
Figure 3: Time course of change from baseline in SIB score for patients who completed 28 weeks of treatment.
Figure 4 shows the cumulative percentages of patients in each treatment group who achieved at least the measure of change in SIB score shown on the x-axis. The curves show that both patients assigned to NAMENDA and placebo have a wide range of responses and generally worsen, but that the NAMENDA group tends to show less worsening or improvement.
Figure 4: Cumulative percentage of patients completing 28 weeks of double-blind treatment with specific changes from baseline in SIB scores.
Study 2 (24-week study)
A 24-week study enrolled 404 patients with probable moderate to severe Alzheimer's disease (diagnosed according to NINCDS-ADRDA criteria, with minimum mental state examination scores ≥5 and ≤14) who had been treated with donepezil for at least 6 months who had been on a stable dose of donepezil for the past 3 months were randomized to NAMENDA or placebo while continuing to receive donepezil. In patients randomized to NAMENDA, treatment was initiated with 5 mg once daily and increased weekly by 5 mg/day in divided doses up to a dose of 20 mg/day (10 mg twice daily).
Impact on ADL of ADCS
Figure 5 shows the time course of change in ADCS-ADL score from baseline for the two treatment groups over the 24 weeks of the study. After 24 weeks of treatment, the mean difference in ADCS-ADL change scores for patients treated with NAMENDA/donepezil (combination therapy) compared to patients treated with placebo/donepezil (monotherapy) was 1.6 units. . Based on a LOCF analysis, treatment with NAMENDA/donepezil was statistically significantly superior to placebo/donepezil.
Figure 5: Time course of change from baseline in ADCS-ADL score for patients who completed 24 weeks of treatment.
Figure 6 shows the cumulative percentage of patients in each of the treatment groups who achieved at least the level of improvement in ADCS-ADL shown on the x-axis. The curves show that patients allocated to NAMENDA/donepezil and placebo/donepezil show a wide range of responses and generally worsen, but the NAMENDA/donepezil group is more likely to show less of a decline or improvement.
Figure 6: Cumulative percentage of patients completing 24 weeks of double-blind treatment with specific changes from baseline in ADCS-ADL scores.
Effects on the SIB
Figure 7 shows the time course of change in SIB score from baseline for the two treatment groups over the 24 weeks of the study. After 24 weeks of treatment, the mean difference in SIBchange scores for NAMENDA/donepezil-treated patients compared with placebo/donepezil-treated patients was 3.3 units. Based on a LOCF analysis, treatment with NAMENDA/donepezil was statistically significantly superior to placebo/donepezil.
Figure 7: Time course of change from baseline in SIB score for patients who completed 24 weeks of treatment.
Figure 8 shows the cumulative percentages of patients in each treatment group who achieved at least the measure of improvement in SIB score shown on the x-axis. The curves show that both patients assigned to NAMENDA/donepezil and placebo/donepezil had a wide range of responses, but that the NAMENDA/donepezil group showed more or less improvement.
Figure 8: Cumulative percentage of patients completing 24 weeks of double-blind treatment with specific changes from baseline in SIB scores.
Study 3 (12 week study)
In a 12-week double-blind study conducted in nursing homes in Latvia, 166 patients had dementiaDSM-III-R, Mini-Mental State Examination Score von <10 y Global Deterioration Scalestaging5 to 7 were randomized to NAMENDA or placebo. In patients randomized to NAMENDA, treatment was initiated with 5 mg once daily and increased to 10 mg once daily after 1 week. The primary measures of efficacy were the Behavioral RatingScale for Geriatrics (BGP) caregiver subscale, a measure of daily functioning, and a Clinical Global Impression of Change (CGI-C), a measure of overall clinical impact. No valid measure of cognitive function was used in this study. A statistically significant treatment difference in favor of NAMENDA versus placebo was observed at 12 weeks for both primary efficacy parameters. Because the patients who entered were a mix of Alzheimer's andvascular dementia, an attempt was made to distinguish the two groups, and it was then stated that all patients had one of the two groups.vascularDementia or Alzheimer's disease, according to Hachinski Ischemia Scale scores at study entry. Only about 50% of the patients hadcomputed tomographyFor the subgroup termed Alzheimer's disease, a statistically significant treatment effect in favor of NAMENDA over placebo was observed at 12 weeks in both BGP and CGI-C.