CLINICAL PHARMACOLOGY
Mechanism of Action
Pathological changes in Dementia of the Alzheimer type involve
cholinergic neuronal pathways that project from the basal
forebrain to the cerebral cortex and hippocampus. These
pathways are thought to be intricately involved in memory,
attention, learning, and other cognitive processes. While
the precise mechanism of rivastigmine's action is unknown,
it is postulated to exert its therapeutic effect by enhancing
cholinergic function. This is accomplished by increasing
the concentration of acetylcholine through reversible inhibition
of its hydrolysis by cholinesterase. If this proposed mechanism
is correct, Exelon's effect may lessen as the disease process
advances and fewer cholinergic neurons remain functionally
intact. There is no evidence that rivastigmine alters the
course of the underlying dementing process. After a 6-mg
dose of rivastigmine, anticholinesterase activity is present
in CSF for about 10 hours, with a maximum inhibition of
about 60% five hours after dosing.
Clinical Trial Data
The effectiveness of Exelon® (rivastigmine tartrate)
as a treatment for Alzheimer's Disease is demonstrated
by the results of two randomized, double-blind, placebo-controlled
clinical investigations in patients with Alzheimer's Disease
[diagnosed by NINCDS-ADRDA and DSM-IV criteria, Mini-Mental
State Examination (MMSE) =10 and =26, and the Global Deterioration
Scale (GDS)]. The mean age of patients participating in
Exelon trials was 73 years with a range of 41-95. Approximately
59% of patients were women and 41% were men. The racial
distribution was Caucasian 87%, Black 4% and Other races
9%.
Study Outcome Measures: In each study, the effectiveness
of Exelon was evaluated using a dual outcome assessment
strategy.
The ability of Exelon to improve cognitive performance
was assessed with the cognitive subscale of the Alzheimer's
Disease Assessment Scale (ADAS-cog), a multi item instrument
that has been extensively validated in longitudinal cohorts
of Alzheimer's Disease patients. The ADAS-cog examines
selected aspects of cognitive performance including elements
of memory, orientation, attention, reasoning, language
and praxis. The ADAS-cog scoring range is from 0 to 70,
with higher scores indicating greater cognitive impairment.
Elderly normal adults may score as low as 0 or 1, but
it is not unusual for non-demented adults to score slightly
higher.
The patients recruited as participants in each study
had mean scores on ADAS-cog of approximately 23 units,
with a range from 1 to 61. Experience gained in longitudinal
studies of ambulatory patients with mild to moderate Alzheimer's
Disease suggest that they gain 6-12 units a year on the
ADAS-cog. Lesser degrees of change, however, are seen
in patients with very mild or very advanced disease because
the ADAS-cog is not uniformly sensitive to change over
the course of the disease. The annualized rate of decline
in the placebo patients participating in Exelon trials
was approximately 3-8 units per year.
The ability of Exelon to produce an overall clinical
effect was assessed using a Clinician's Interview Based
Impression of Change that required the use of caregiver
information, the CIBIC-Plus. The CIBIC-Plus is not a single
instrument and is not a standardized instrument like the
ADAS-cog. Clinical trials for investigational drugs have
used a variety of CIBIC formats, each different in terms
of depth and structure. As such, results from a CIBIC-Plus
reflect clinical experience from the trial or trials in
which it was used and can not be compared directly with
the results of CIBIC-Plus evaluations from other clinical
trials. The CIBIC-Plus used in the Exelon trials was a
structured instrument based on a comprehensive evaluation
at baseline and subsequent time-points of three domains:
patient cognition, behavior and functioning, including
assessment of activities of daily living. It represents
the assessment of a skilled clinician using validated
scales based on his/her observation at interviews conducted
separately with the patient and the caregiver familiar
with the behavior of the patient over the interval rated.
The CIBIC-Plus is scored as a seven point categorical
rating, ranging from a score of 1, indicating "markedly
improved," to a score of 4, indicating "no change"
to a score of 7, indicating "marked worsening."
The CIBIC-Plus has not been systematically compared directly
to assessments not using information from caregivers (CIBIC)
or other global methods.
U.S. Twenty-Six-Week Study
In a study of 26 weeks duration, 699 patients were randomized
to either a dose range of 1-4 mg or 6-12 mg of Exelon
per day or to placebo, each given in divided doses. The
26-week study was divided into a 12-week forced dose titration
phase and a 14-week maintenance phase. The patients in
the active treatment arms of the study were maintained
at their highest tolerated dose within the respective
range.
Global Twenty-Six-Week Study
In a second study of 26 weeks duration, 725 patients were
randomized to either a dose range of 1-4 mg or 6-12 mg
of Exelon per day or to placebo, each given in divided
doses. The 26-week study was divided into a 12-week forced
dose titration phase and a 14-week maintenance phase.
The patients in the active treatment arms of the study
were maintained at their highest tolerated dose within
the respective range.
U.S. Fixed Dose Study
In a study of 26 weeks' duration, 702 patients were randomized
to doses of 3, 6, or 9 mg/day of Exelon or to placebo,
each given in divided doses. The fixed-dose study design,
which included a 12-week forced titration phase and a
14-week maintenance phase, led to a high dropout rate
in the 9 mg/day group because of poor tolerability. At
26 weeks of treatment, significant differences were observed
for the ADAS-cog mean change from baseline for the 9 mg/day
and 6 mg/day groups, compared to placebo. No significant
differences were observed between any of the Exelon dose
groups and placebo for the analysis of the CIBIC-Plus
mean rating of change. Although no significant differences
were observed between Exelon treatment groups, there was
a trend toward numerical superiority with higher doses.
Age, Gender and Race: Patient's age, gender, or race
did not predict clinical outcome to Exelon treatment.
Pharmacokinetics
Rivastigmine is well absorbed with absolute bioavailability
of about 40% (3-mg dose). It shows linear pharmacokinetics
up to 3 mg BID but is non-linear at higher doses. Doubling
the dose from 3 to 6 mg BID results in a 3-fold increase
in AUC. The elimination half-life is about 1.5 hours,
with most elimination as metabolites via the urine.
Absorption: Rivastigmine is
rapidly and completely absorbed. Peak plasma concentrations
are reached in approximately 1 hour. Absolute bioavailability
after a 3-mg dose is about 36%. Administration of Exelon
with food delays absorption (t max ) by 90 min, lowers
C max by approximately 30% and increases AUC by approximately
30%.
Distribution: Rivastigmine
is widely distributed throughout the body with a volume
of distribution in the range of 1.8-2.7 L/kg. Rivastigmine
penetrates the blood brain barrier, reaching CSF peak
concentrations in 1.4-2.6 hours. Mean AUC 1-12hr ratio
of CSF/plasma averaged 40 ± 0.5% following 1-6
mg BID doses.
Rivastigmine is about 40% bound to plasma proteins at
concentrations of 1-400 ng/mL, which cover the therapeutic
concentration range. Rivastigmine distributes equally
between blood and plasma with a blood-to-plasma partition
ratio of 0.9 at concentrations ranging from 1-400 ng/mL.
Metabolism: Rivastigmine is
rapidly and extensively metabolized, primarily via cholinesterase-mediated
hydrolysis to the decarbamylated metabolite. Based on
evidence from in vitro and animal studies the major cytochrome
P450 isozymes are minimally involved in rivastigmine metabolism.
Consistent with these observations is the finding that
no drug interactions related to cytochrome P450 have been
observed in humans (see Drug-Drug Interactions ).
Elimination: The major pathway
of elimination is via the kidneys. Following administration
of 14 C-rivastigmine to 6 healthy volunteers total recovery
of radioactivity over 120 hours was 97% in urine and 0.4%
in feces. No parent drug was detected in urine. The sulfate
conjugate of the decarbamylated metabolite is the major
component excreted in urine and represents 40% of the
dose. Mean oral clearance of rivastigmine is 1.8 ±
0.6 L/min after 6 mg BID.
Special Populations
Hepatic Disease: Following a
single 3-mg dose, mean oral clearance of rivastigmine
was 60% lower in hepatically impaired patients (n=10,
biopsy proven) than in healthy subjects (n=10). After
multiple 6 mg BID oral dosing, the mean clearance of rivastigmine
was 65% lower in mild (n=7, Child-Pugh score 5-6) and
moderate (n=3, Child-Pugh score 7-9) hepatically impaired
patients (biopsy proven, liver cirrhosis) than in healthy
subjects (n=10). Dosage adjustment is not necessary in
hepatically impaired patients as the dose of drug is individually
titrated to tolerability.
Renal Disease: Following a
single 3-mg dose, mean oral clearance of rivastigmine
is 64% lower in moderately impaired renal patients (n=8,
GFR=10-50 mL/min) than in healthy subjects (n=10, GFR
=60 mL/min); Cl/F=1.7 L/min (cv=45%) and 4.8 L/min (cv=80%),
respectively. In severely impaired renal patients (n=8,
GFR<10 mL/min), mean oral clearance of rivastigmine
is 43% higher than in healthy subjects (n=10, GFR =60
mL/min); Cl/F=6.9 L/min and 4.8 L/min, respectively. For
unexplained reasons, the severely impaired renal patients
had a higher clearance of rivastigmine than moderately
impaired patients. However, dosage adjustment may not
be necessary in renally impaired patients as the dose
of the drug is individually titrated to tolerability.
Age: Following a single 2.5
mg oral dose to elderly volunteers (>60 years of age,
n=24) and younger volunteers (n=24), mean oral clearance
of rivastigmine was 30% lower in elderly (7 L/min) than
in younger subjects (10 L/min).
Gender and Race: No specific
pharmacokinetic study was conducted to investigate the
effect of gender and race on the disposition of Exelon,
but a population pharmacokinetic analysis indicates that
gender (n=277 males and 348 females) and race (n=575 White,
34 Black, 4 Asian, and 12 Other) did not affect the clearance
of Exelon.
Nicotine Use: Population PK
analysis showed that nicotine use increases the oral clearance
of rivastigmine by 23% (n=75 Smokers and 549 Nonsmokers).
Drug-Drug Interactions
Effect of Exelon on the Metabolism of OtherDrugs: Rivastigmine
is primarily metabolized through hydrolysis by esterases.
Minimal metabolism occurs via the major cytochrome P450
isoenzymes. Based on in vitro studies, no pharmacokinetic
drug interactions with drugs metabolized by the following
isoenzyme systems are expected: CYP1A2, CYP2D6, CYP3A4/5,
CYP2E1, CYP2C9, CYP2C8, or CYP2C19.
No pharmacokinetic interaction was observed between rivastigmine
and digoxin, warfarin, diazepam, or fluoxetine in studies
in healthy volunteers. The elevation ofprothrombin time
induced by warfarin is not affected by administration
of Exelon.
Effect of Other Drugs on the Metabolism of
Exelon: Drugs that induce or inhibit CYP450
metabolism are not expected to alter the metabolism of
rivastigmine. Single dose pharmacokinetic studies demonstrated
that the metabolism of rivastigmine is not significantly
affected by concur-rent administration of digoxin, warfarin,
diazepam, or fluoxetine.
Population PK analysis with a database of 625 patients
showed that the pharmacokinetics of rivastigmine were
not influenced by commonly prescribed medications such
as antacids (n=77), antihypertensives (n=72), (beta)-blockers
(n=42), calcium channel blockers (n=75), antidiabetics
(n=21), nonsteroidal anti-inflammatory drugs (n=79), estrogens
(n=70), salicylate analgesics (n=177), antianginals (n=35),
and antihistamines (n=15). In addition, in clinical trials,
no increased risk of clinically relevant untoward effects
was observed in patients treated concomitantly with Exelon
and these agents.
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