CLINICAL PHARMACOLOGY
Mechanism of Action
Pathological changes in dementia of the Alzheimer’s type and
dementia associated with Parkinson’s disease 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% 5 hours after dosing.
In vitro and in
vivo studies demonstrate that the inhibition of cholinesterase by
rivastigmine is not affected by the concomitant administration of memantine, an
N-methyl-D-aspartate receptor antagonist.
Clinical Trial Data
Dementia of the Alzheimer’s
T
ype
The effectiveness of Exelon® (rivastigmine
tartrate) as a treatment for Alzheimer's disease is demonstrated by the results
of 2 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) greater than or equal to 10 and less than or equal to 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 suggests 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 (CIBIC) 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 cannot 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 7-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 or other global methods.
U.S. 26-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.
Effects on the ADAS-cog: Figure 1 illustrates
the time course for the change from baseline in ADAS-cog scores for all three
dose groups over the 26 weeks of the study. At 26 weeks of treatment, the mean
differences in the ADAS-cog change scores for the Exelon-treated patients
compared to the patients on placebo were 1.9 and 4.9 units for the 1-4 mg and
6-12 mg treatments, respectively. Both treatments were statistically
significantly superior to placebo and the 6-12 mg/day range was significantly
superior to the 1-4 mg/day range.
Figure 1: Time-course of the Change from
Baseline in ADAS-cog Score for Patients Completing 26 Weeks of
Treatment
Figure 2 illustrates the cumulative percentages of patients from each
of the three treatment groups who had attained at least the measure of
improvement in ADAS-cog score shown on the X axis. Three change scores, (7-point
and 4-point reductions from baseline or no change in score) have been identified
for illustrative purposes, and the percent of patients in each group achieving
that result is shown in the inset table.
The curves demonstrate that both patients assigned to Exelon and
placebo have a wide range of responses, but that the Exelon groups are more
likely to show the greater improvements. A curve for an effective treatment
would be shifted to the left of the curve for placebo, while an ineffective or
deleterious treatment would be superimposed upon, or shifted to the right of the
curve for placebo, respectively.
Figure 2: Cumulative Percentage of Patients
Completing 26 Weeks of Double-blind Treatment with Specified Changes from
Baseline ADAS-cog Scores. The Percentages of Randomized Patients who Completed
the Study were: Placebo 84%, 1-4 mg 85%, and 6-12 mg 65%.
Effects on the CIBIC-Plus: Figure 3 is a
histogram of the frequency distribution of CIBIC-Plus scores attained by
patients assigned to each of the three treatment groups who completed 26 weeks
of treatment. The mean Exelon-placebo differences for these groups of patients
in the mean rating of change from baseline were 0.32 units and 0.35 units for
1-4 mg and 6-12 mg of Exelon, respectively. The mean ratings for the 6-12 mg/day
and 1-4 mg/day groups were statistically significantly superior to placebo. The
differences between the 6-12 mg/day and the 1-4 mg/day groups were statistically
significant.
Figure 3: Frequency Distribution of CIBIC-Plus
Scores at Week 26
Global 26-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.
Effects on the ADAS-cog: Figure 4 illustrates
the time course for the change from baseline in ADAS-cog scores for all three
dose groups over the 26 weeks of the study. At 26 weeks of treatment, the mean
differences in the ADAS-cog change scores for the Exelon-treated patients
compared to the patients on placebo were 0.2 and 2.6 units for the 1-4 mg and
6-12 mg treatments, respectively. The 6-12 mg/day group was statistically
significantly superior to placebo, as well as to the 1-4 mg/day group. The
difference between the 1-4 mg/day group and placebo was not statistically
significant.
Figure 4: Time-course of the Change from
Baseline in ADAS-cog Score for Patients Completing 26 Weeks of
Treatment
Figure 5 illustrates the cumulative percentages of patients from each
of the three treatment groups who had attained at least the measure of
improvement in ADAS-cog score shown on the X axis. Similar to the U.S. 26-week
study, the curves demonstrate that both patients assigned to Exelon and placebo
have a wide range of responses, but that the 6-12 mg/day Exelon group is more
likely to show the greater improvements.
Figure 5: Cumulative Percentage of Patients
Completing 26 Weeks of Double-blind Treatment with Specified Changes from
Baseline ADAS-cog Scores. The Percentages of Randomized Patients who Completed
the Study were: Placebo 87%, 1-4 mg 86%, and 6-12 mg 67%.
Effects on the CIBIC-Plus: Figure 6 is a
histogram of the frequency distribution of CIBIC-Plus scores attained by
patients assigned to each of the three treatment groups who completed 26 weeks
of treatment. The mean Exelon-placebo differences for these groups of patients
for the mean rating of change from baseline were 0.14 units and 0.41 units for
1-4 mg and 6-12 mg of Exelon, respectively. The mean ratings for the 6-12 mg/day
group were statistically significantly superior to placebo. The comparison of
the mean ratings for the 1-4 mg/day group and placebo group was not
statistically significant.
Figure 6: Frequency Distribution of CIBIC-Plus
Scores at Week 26
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-dose 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.
Dementia Associated with
Parkinson’s
D
isease (PDD)
International
24
-Week Study
The effectiveness of Exelon as a treatment for dementia
associated with Parkinson’s disease is demonstrated by the results of one
randomized, double-blind, placebo-controlled clinical investigation in patients
with mild to moderate dementia, with onset at least 2 years after the initial
diagnosis of idiopathic Parkinson’s disease. The diagnosis of idiopathic
Parkinson’s disease was based on the United Kingdom Parkinson’s Disease Society
Brain Bank clinical criteria. The diagnosis of dementia was based on the
criteria stipulated under the DSM-IV category “Dementia Due To Other General
Medical Condition” (code 294.1x), but patients were not required to have a
distinctive pattern of cognitive deficits as part of the dementia. Alternate
causes of dementia were excluded by clinical history, physical and neurological
examination, brain imaging, and relevant blood tests. Patients enrolled in the
study had a MMSE score greater than or equal to 10 and less than or equal to 24 at entry. The mean age of patients
participating in this trial was 72.7 years with a range of 50–91. Approximately,
35.1% of patients were women and 64.9% of patients were men. The racial
distribution was 99.6% Caucasian and other races 0.4%.
Study Outcome Measures
This study used a dual outcome assessment strategy to evaluate the
effectiveness of Exelon.
The ability of Exelon to improve cognitive performance was assessed
with the ADAS-cog.
The ability of Exelon to produce an overall clinical effect was
assessed using the Alzheimer’s Disease Cooperative Study – Clinician’s Global
Impression of Change (ADCS-CGIC). The ADCS-CGIC is a more standardized form of
CIBIC-Plus and is also scored as a 7-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."
Study Results
In this study, 541 patients were randomized to a dose range of 3–12 mg of
Exelon per day or to placebo in a ratio of 2:1, given in divided doses. The
24-week study was divided into a 16-week titration phase and an 8-week
maintenance phase. The patients in the active treatment arm of the study were
maintained at their highest tolerated dose within the specified dose range.
Effects on the ADAS-cog: Figure 7 illustrates
the time course for the change from baseline in ADAS-cog scores for both
treatment groups over the 24-week study. At 24 weeks of treatment, the mean
difference in the ADAS-cog change scores for the Exelon-treated patients
compared to the patients on placebo was 3.8 points. This treatment difference
was statistically significant in favor of Exelon when compared to placebo.
Figure 7:Time Course of the Change from Baseline in
ADAS-cog Score for Patients Completing 24 Weeks of Treatment
Effects on the ADCS-CGIC: Figure 8 is a
histogram of the distribution of patients’ scores on the ADCS-CGIC (Alzheimer’s
Disease Cooperative Study - Clinician’s Global Impression of Change) at 24
weeks. The mean difference in change scores between the Exelon and placebo
groups from baseline was 0.5 points. This difference was statistically
significant in favor of Exelon treatment.
Figure 8:Distribution of ADCS-CGIC Scores for
Patients Completing 24 Weeks of Treatment
Age, Gender and Race
Patients’ age, gender, or race did not predict clinical outcome of 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 (tmax) by 90 minutes,
lowers Cmax 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 AUC1-12hr 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 14C-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 greater than or equal to 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 less than 10 mL/min), mean oral clearance
of rivastigmine is 43% higher than in healthy subjects (n=10, GFR greater than or equal to 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 (greater than 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
Other Drugs: 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 of prothrombin 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 concurrent 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), ß-blockers
(n=42), calcium channel blockers (n=75), antidiabetics (n=21), nonsteroidal
antiinflammatory 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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