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 MerzPharmaceuticals 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 cationchannels.

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 ROUTEOF 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 Magnesium stearate.

Dispensed: Rx only

Pharmacol. Category/Indication: Moderate to severe AD

Dosage forms: Tablets

Strengths: 5, 10, 15, 20 mg

Route of administration : Oral