LCSP - MEMANTINE:

2. PRECLINICAL
Marjan Stosic
Product Profile
Mechanism of action
Animal model data
Efficacy
PK data
Toxicity studies
IND package studies
Pharmaceutics, dosage forms and route of
administration
PRODUCT PROFILE
Namenda (memantine hydrochloride) is an orally
active NMDA receptor antagonist.
1-amino-3,5-dimethyladamantane hydrochloride
Memantine has been developed by Merz
Pharmaceuticals and its approved in Europe and the
USA for the treatment of moderate to severe
Alzheimer's disease.
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
Alzheimers 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.
MECHANISM OF ACTION
ANIMAL MODEL DATA
These studies were conducted to eveluate the
mechanism of action of memantine, and to support
the proposed therapeutic indication.
Safety pharmacology studies were conducted in
mice, rats and dogs, to include eveluation of
memantine effects on CNS, cardiovascular,
respiratory, gastrointestinal and renal function.
Pharmacokinetic analyses were performed in mice,
rats, rabbits, dogs and baboons, and included
characterization of oral bioavailibility and ADME
parameters.
EFFICACY
Memantine demonstrated activity in animals related
to the proposed indication in experimental
paradigms of neuroprotection and memory
enhancement.
Memantine shortened the time to return to
consciousness in animal models of head injury,
decreases the number of trials on retention session in
anoxia-treated mice, improved learning in rats with
internal capsule lesions, and antagonized the
disturbed EEG patterns in pons ischemic rats.
PHARMACOKINETIC DATA
Orally administered memantine HCl is rapidly and
completely absorbed, and shows extensive tissue
distribution in animals, crosses the blood barrier and
placenta, and binds to melanin.
Metabolism is by hydroxylation, N-oxidation and
conjugation, and the metabolic profiles are similar in
mice, rats, baboons and humans.
Memantine is nearly completely excreted as parent
drug and conjugated metabolites in the urine, within
48 hours in rodents, rabbits, dogs, pigs and baboons.
TOXICITY STUDIES
The acute toxicity of memantine was low in animals
(LD50 values approximately 500 mg/kg in rodents
and 50 mg/kg in dogs) and included ataxia, tremor,
bradypnea, dyspnea, muscular hypotonia and
convulsions at very high doses.
At high doses memantine had notable CNS effects,
including CNS excitation, decreased indices of
awareness and motor activity.
Mementine slightly reduces blood pressure in dogs
and inhibited gastorintestinal activity in rodents.
Subchronic and chronic high dose was associated
with CNS effects, reduced body weight gain and food
consumption, and toxicity in the kidney and eyes.
TOXICITY STUDIES
Memantine was not mutagenic in the Ames test,
human lymphocytes, rats spermatocytes and in the
mouse micronucleus test.
No evidence of carcinogenic potential was found in 2-
year feeding studies in mice and rats.
Memantine has no adverse effects on male and
female fertility and reproductive performance in rats,
teratogenicity in rats and rabbits, and perinatal or
postnatal development in rats.
In special toxicology eveluations, ocular toxicity was
indicated by cataract formation in pigmented but not
in albino rats.
IND PACKAGE STUDIES
Examination of the infulence on several
cardiovascular parameters and the respiration in
anesthetised beagle dogs.
Subacute oral toxicity study in the dog (3 months)
Six month chronic oral toxicity stud in dogs.
Examination of the influence on intestinal motility
following oral administration in rats.
Examination for spasmolytic or spasmogenic
properties in the isolated guinea pig ileum.
Six week oral comparative stud in the pigmented and
albino rat.
IND PACKAGE STUDIES
13-week oral toxicity study in the rat, followed by a 4-
week tretament free period.
Report and expert statement on histological specimen
from 13-week subchronic toxicity stud on rats fed a
memantine containing diet.
Chronic 12 month oral toxicity stud with D145 in the rat.
52-week oral toxicity study in the rat followed by a 6-
week tretament free period.
13-week oral toxicity study in baboons with 4-week
withdrawal period.
Toxicity to baboons by repeated oral administration for
52 weeks followed by a 4-week withdrawal period.
PHARMACEUTICS, DOSAGE FORMS AND ROUTE
OF ADMINISTRATION
Clinical formulation: Imediate release film-coated
capsule-shaped tablets with the folowing
composition: Memantine HCl, Lactose monohydrate,
Microcrystalline Cellulose, Colloidal silicon dioxide,
Talc and Magnesiumstearate.
Dispensed: Rx only
Pharmacol. Category/Indication: Moderate to severe
AD
Dosage forms: Tablets
Strengths: 5, 10, 15, 20 mg
Route of administration : Oral