LCSP - Memantine: 3. Early Clinical Development
LCSP - Memantine: 3. Early ClinicalDevelopmentMarjan Stosic
Early Stage Development in HumansPhase one safety study
Phase two studies Dose ranging studies Formulation and dose
regimenThere are 25 pharmacodynamic/pharmacokinetic studies with
memantine.
These studies have included 434 subjects, 377 of them received
memantine and 105 received placebo.
Of these clinical pharmacology studies, 2 were performed in
patients with neurological disease/dementia syndrome, 2 in healthy
elderly subjects, one in elderly subjects with renal impairment and
20 in healthy volunteers.
A total of 11 single dose studies have been performed, with
memantine administered orally or intravenously at doses up to 60
mg. The remaining 14 studies were multiple-dose studies, with doses
of memantine up to 60 mg orally.Phase one safety study - Effects on
Central Nervous SystemTwenty-four healthy subjects (age range 20 to
35 years) received a single dose of 30 mg memantine or placebo and
were tested for choice reaction time, visual flicker fusion
frequency, subjective well-being (including 10-point verbal scales
for agitated, alert, mood, tired, relaxed, focused, energetic),
sleep quality, and long-term, short-term and everyday memory.
(MRZ-9405) Memantine had no effect on temporal information
processing or on short-term and long-term memory functions in these
healthy subjects. Based on the wellbeing scale, subjects in the
memantine group had an increase in perceived tiredness and a
decrease in subjective alertness relative to placebo treatment.
Phase one safety study - Effects on Central Nervous SystemNo
consistent effects of memantine on EEG were obtained in a study
with memantine 30 mg iv (MRZ-8610).
In another study in elderly subjects, a decrease of vigilance
under placebo and stabilisation under memantine was observed (MRZ-
8909).
The relative absence of effects of memantine on memory functions
and information processing in healthy subjects are in agreement
with the mode of action of the drug as a low-moderate affinity,
uncompetitive, voltage-dependent NMDA receptor antagonist.
Phase one safety study - endocrine systemThe effect of memantine
on the endocrine system was investigated in two trials.
One study evaluated the effects of memantine and another NMDA
receptor antagonist, ketamine , relative to placebo treatment in 15
healthy male subjects.
Memantine had no effect on serum cortisol or prolactin levels
relative to placebo treatment while ketamine increased the levels
of both of these hormones.Phase one safety study - endocrine
systemIn another study, the effect of memantine on pituitary
function was evaluated in 49 healthy elderly subjects who received
multiple daily doses of 20 mg memantine as immediate release
tablets or sustained release tablets.
Memantine had no effect on pituitary function as measured by
TSH, LH, FSH, prolactin, and vasopressin levels. (MRZ-9402)
Phase one safety study - HemodynamicTwo studies were performed
exploring the dose-effect of memantine on cardiovascular function
in a total of 9 healthy volunteers.
With single doses of memantine up to 60 mg i.v. (MRZ-Z040)
small, non dose-dependent decreases in cardiac performance index
and systolic blood pressure were observed.
In another small study (MRZ-Z041) an increase in blood pressure
had also been observed.Phase one safety study - HemodynamicThe
results of these pharmacology studies (MRZ-Z040/Z041) do not show
any significant difference between placebo and memantine on blood
pressure. No effects on cardiac conduction were found with
memantine in clinical pharmacology studies.
Phase one safety study - Adverse eventsThe reported adverse
events were: - tiredness, - headache, - dizziness, - somnolence, -
impaired concentration, - dry mouth, - agitation and - nausea.
Phase two studiesThe 21 studies of memantine in 3109 patients
with dementia or dementia syndrome examined doses of memantine of
10-30 mg per day. Fourteen of the studies were double blind, 2
blind different-dose studies and 5 were open or drug monitoring
studies. Memantine showed a statistically significant benefit in
all pilot studies involving more than 65 patients. In summary, 7 of
the 12 placebo controlled pilot studies showed statistically
significant improvements in cognitive tests and behavioural
evaluations, and 5 were negative.Phase two studies Dose ranging
studiesThere is no formal placebo-controlled dose ranging study in
the clinical development program of memantine.
The choice of memantine 20 mg daily as a target for the phase
III trials is supported by a dose finding analysis (MRZ-9501),
which included one pharmacokinetic study (n=24) and 5 of the pilot
studies in dementia syndrome (n=575).Phase two studies Dose ranging
studiesThis analysis showed a dose response across the range of
memantine 10 mg to 30 mg daily (and in a small number of patients
on 60 mg), with more pronounced improvement in Sandoz Clinical
Assessment Geriatric Scale (SCAG) with increasing dose, but with a
dose-dependent increase in the number of AEs.
This dose dependent increase in AEs was reduced when the daily
dose was titrated up gradually. Phase two studies Dose ranging
studiesThere are additional data from a long-term tolerability and
safety trial (9406) in patients with impaired cerebral functional
capacity.
Study 9406 was performed in 147 patients, who were divided in
three groups receiving different dosing regimens. It had a high
number of dropouts by reasons apparently not related with the
medication. These adverse events increased in frequency with 30 mg
and 60 mg (11% and 18%) with respect to 15 mg (0%).
Phase two studies Formulation and dose regimenFormulation: -
Film-Coated Tablets - Oral Drops Solution
Dose regimen: - Memantine-HCl tablets administered orally 2 x 10
mg/day
