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Anti-dementia.
Pharmacology: There is increasing evidence that malfunctioning of glutamatergic neurotransmission, in particular at NMDA-receptors, contributes to both expression of symptoms and disease progression in neurodegenerative dementia.
Memantine is a voltage-dependent, moderate-affinity uncompetitive NMDA-receptor antagonist. It modulates the effects of pathologically elevated tonic levels of glutamate that may lead to neuronal dysfunction.
Clinical Studies: A clinical trial in a population of patients suffering from moderate to severe Alzheimer's disease (MMSE total scores at baseline of 3-14) showed beneficial effects of memantine treatment in comparison to placebo over a treatment period of 6 months.
In this multicenter, double-blind, randomized, placebo-controlled study, a total of 252 outpatients (33% male, 67% female, mean age 76 years) were included. The dosing was 10 mg memantine twice a day. Primary outcome parameters included assessment of the global domain [using the Clinicians Interview-Based Impression of Change (CIBIC-Plus)] and the functional domain [using the Activities of Daily Living Inventory (ADCS-ADLsev)]. Cognition was assessed as a secondary endpoint with the Severe Impairment Battery (SIB). The results in these domains favoured memantine over placebo (Observed Cases Analysis for CIBIC-Plus: p=0.025; ADCS-ADLsev: p=0.003; SIB: p=0.002).
After 6 months, the rate of individual responders (response prospectively defined as stabilization or improvement in 2 independent domains) was 29% for the memantine group versus 10% for placebo (p=0.0004). With a triple criterion (response defined as stabilization or improvement in all 3 domains: Cognition, functional and global domain), there were 11% responders for memantine versus 6% for placebo (p=0.17).
Pharmacokinetics: Absorption: Memantine has an absolute bioavailability of approximately 100%. Tmax is between 3 and 8 hrs. There is no indication that food influences the absorption of memantine.
Linearity: Studies in volunteers have demonstrated linear pharmacokinetics in the dose range of 10-40 mg.
Distribution: Daily doses of 20 mg lead to steady-state plasma concentrations of memantine ranging from 70-150 ng/mL (0.5-1 micromole) with large interindividual variations. When daily doses of 5-30 mg were administered, a mean CSF/serum ratio of 0.52 was calculated. The volume of distribution is around 10 L/kg. About 45% of memantine is bound to plasma proteins.
Biotransformation: In man, about 80% of the circulating memantine-related material is present as the parent compound. Main human metabolites are N-3,5-dimethyl-gludantan, the isomeric mixture of 4- and 6-hydroxy-memantine, and 1-nitroso-3,5-dimethyl-adamantane. None of these metabolites exhibit NMDA-antagonistic activity. No cytochrome P-450 catalyzed metabolism has been detected in vitro.
In a study using orally administered 14C-memantine, a mean of 84% of the dose was recovered within 20 days, >99% being excreted renally.
Elimination: Memantine is eliminated in a monoexponential manner with a terminal t½ of 60-100 hrs. In volunteers with normal kidney function, total clearance (Cltot) amounts to 170 mL/min/1.73 m2 and part of total renal clearance is achieved by tubular secretion.
Renal handling also involves tubular reabsorption, probably mediated by cation transport proteins. The renal elimination rate of memantine under alkaline urine conditions may be reduced by a factor of 7-9 (see Precautions). Alkalization of urine may result from drastic changes in diet eg, from a carnivore to a vegetarian diet, or from the massive ingestion of alkalizing gastric buffers.
Specific Patient Population: In elderly volunteers with normal and reduced renal function (CrCl of 50-100 mL/min/1.73 m2), a significant correlation was observed between CrCl and total renal clearance of memantine (see Dosage & Administration).
The effect of liver disease on the pharmacokinetics of memantine has not been studied. As memantine is metabolized to a minor extent only, and into metabolites with no NMDA-antagonistic activity, clinically relevant changes in the pharmacokinetics are not expected in mild to moderate liver impairment.
Pharmacokinetic/Pharmacodynamic Relationship: At a dose of memantine of 20 mg/day the cerebrospinal fluid (CSF) levels match the ki-value (ki=inhibition constant) of memantine, which is 0.5 micromole in human frontal cortex.
Toxicology: Preclinical Safety Data: In short-term studies in rats, memantine like other NMDA-antagonists has induced neuronal vacuolisation and necrosis (Olney lesions) only after doses leading to very high peak serum concentrations. Ataxia and other preclinical signs have preceded the vacuolisation and necrosis. As the effects have neither been observed in long-term studies in rodents nor in non-rodents, the clinical relevance of these findings is unknown.
Ocular changes were inconsistently observed in repeated dose toxicity studies in rodents and dogs, but not in monkeys. Specific ophthalmoscopic examinations in clinical studies with memantine did not disclose any ocular changes.
Phospholipidosis in pulmonary macrophages due to accumulation of memantine in lysosomes was observed in rodents. This effect is known from other drugs with cationic amphiphilic properties. There is a possible relationship between this accumulation and the vacuolisation observed in lungs. This effect was only observed at high doses in rodents. The clinical relevance of these findings is unknown.
No genotoxicity has been observed following testing of memantine in standard assays. There was no evidence of any carcinogenicity in life-long studies in mice and rats. Memantine was not teratogenic in rats and rabbits, even at maternally toxic doses, and no adverse effects of memantine were noted on fertility. In rats, foetal growth reduction was noted at exposure levels which are identical or slightly higher than at human exposure.
