Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: psychoanaleptics, anticholinesterases; ATC-code: N06DA03.
Rivastigmine is an acetyl- and butyrylcholinesterase inhibitor of the carbamate type, thought to facilitate cholinergic neurotransmission by slowing the degradation of acetylcholine released by functionally intact cholinergic neurones. Thus, rivastigmine may have an ameliorative effect on cholinergic-mediated cognitive deficits in dementia associated with Alzheimer’s disease and Parkinson’s disease.
Rivastigmine interacts with its target enzymes by forming a covalently bound complex that temporarily inactivates the enzymes. In healthy young men, an oral 3.0 mg dose decreases acetylcholinesterase (AChE) activity in cerebro spinal fluid (CSF) by approximately 40% within the first 1.5 hours after administration. Activity of the enzyme returns to baseline levels about 9 hours after the maximum inhibitory effect has been achieved. In patients with Alzheimer’s Disease (AD), inhibition of acetylcholinesterase in CSF by rivastigmine was dose-dependent up to 6 mg given twice daily, the highest dose tested. Inhibition of BuChE activity in CSF of 14 Alzheimer patients treated by rivastigmine was similar to that of AchE.

Clinical studies in Alzheimer’s dementia

The efficacy of rivastigmine has been established through the use of three independent, domain specific, assessment tools which were assessed at periodic intervals during 6 month treatment periods. These include the ADAS-Cog (Alzheimer’s Disease Assessment Scale – Cognitive subscale, a performance based measure of cognition), the CIBIC-Plus (Clinician’s Interview Based Impression of Change-Plus, a comprehensive global assessment of the patient by the physician incorporating caregiver input), and the PDS (Progressive Deterioration Scale, a caregiver-rated assessment of the activities of daily living including personal hygiene, feeding, dressing, household chores such as shopping, retention of ability to orient oneself to surroundings as well as involvement in activities relating to finances, etc.).

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The patients studied had an MMSE (Mini-Mental State Examination) score of 10–24.
The results for clinically relevant responders pooled from two flexible dose studies out of the three pivotal 26-week multicentre studies in patients with mild-to-moderately severe Alzheimer’s Dementia, are provided in Table 4 below. Clinically relevant improvement in these studies was defined a priori as at least 4-point improvement on the ADAS-Cog, improvement on the CIBIC-Plus, or at least a 10% improvement on the PDS.

In addition, a post-hoc definition of response is provided in the same table. The secondary definition of response required a 4-point or greater improvement on the ADAS-Cog, no worsening on the CIBIC- Plus, and no worsening on the PDS. The mean actual daily dose for responders in the 6–12 mg group, corresponding to this definition, was 9.3 mg. It is important to note that the scales used in this indication vary and direct comparisons of results for different therapeutic agents are not valid.

Table 4

Patients with Clinically Significant Response (%)
Intent to Treat             Last Observation Carried
Forward
Response Measure                 Rivastigmin       Placebo      Rivastigmin        Placebo e 6–12 mg                      e 6–12 mg
N=473          N=472           N=379           N=444
ADAS-Cog: improvement                21***                12           25***                 12 of at least 4 points
CIBIC-Plus: improvement              29***                18           32***                 19 PDS: improvement of at               26***                17           30***                 18 least 10%
At least 4 points                       10*               6            12**                  6 improvement on ADAS-
Cog with no worsening on
CIBIC-Plus and PDS

*p<0.05,             **p<0.01,               ***p<0.001

Clinical studies in dementia associated with Parkinson’s disease
The efficacy of rivastigmine in dementia associated with Parkinson’s disease has been demonstrated in a 24-week multicentre, double-blind, placebo-controlled core study and its 24-week open-label extension phase. Patients involved in this study had an MMSE (Mini-Mental State Examination) score of 10–24. Efficacy has been established by the use of two independent scales which were assessed at regular intervals during a 6-month treatment period as shown in Table 5 below: the ADAS-Cog, a measure of cognition, and the global measure ADCS-CGIC (Alzheimer’s Disease Cooperative Study- Clinician’s Global Impression of Change).

Table 5

Dementia associated            ADAS-Cog          ADAS-Cog        ADCS-            ADCS-CGIC with Parkinson’s Disease       Exelon            Placebo         CGIC             Placebo Exelon

ITT + RDO population           (n=329)           (n=161)         (n=329)          (n=165) 
Mean baseline ± SD             23.8 ± 10.2       24.3 ± 10.5     n/a              n/a Mean change at 24 weeks        2.1 ± 8.2         -0.7 ± 7.5      3.8 ± 1.4        4.3 ± 1.5 ± SD
Adjusted treatment difference                                       1                               n/a 2.88 p-value versus placebo                             1                           0.007 <0.001
2

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ITT - LOCF population       (n=287)            (n=154)       (n=289)          (n=158) 
Mean baseline ± SD          24.0 ± 10.3        24.5 ± 10.6   n/a              n/a Mean change at 24 weeks     2.5 ± 8.4          -0.8 ± 7.5    3.7 ± 1.4        4.3 ± 1.5 ± SD
Adjusted treatment difference                                     1                            n/a 3.54 p-value versus placebo                           1                               2 <0.001                           <0.001

1 Based on ANCOVA with treatment and country as factors and baseline ADAS-Cog as a covariate. A positive change indicates improvement.
2 Mean data shown for convenience, categorical analysis performed using van Elteren test

ITT: Intent-To-Treat; RDO: Retrieved Drop Outs; LOCF: Last Observation Carried Forward 
Although a treatment effect was demonstrated in the overall study population, the data suggested that a larger treatment effect relative to placebo was seen in the subgroup of patients with moderate dementia associated with Parkinson’s disease. Similarly a larger treatment effect was observed in those patients with visual hallucinations (see Table 6).

Table 6

Dementia associated         ADAS-Cog           ADAS-Cog      ADAS-Cog           ADAS-Cog with Parkinson’s Disease    Exelon             Placebo       Exelon             Placebo 
Patients with                    Patients without visual                           visual hallucinations hallucinations
ITT + RDO population        (n=107)        (n=60)            (n=220)            (n=101) 
Mean baseline ± SD          25.4 ± 9.9         27.4 ± 10.4   23.1 ± 10.4        22.5 ± 10.1 Mean change at 24 weeks     1.0 ± 9.2          -2.1 ± 8.3    2.6 ± 7.6          0.1 ± 6.9 ± SD
Adjusted treatment difference                                   1                                1 4.27                             2.09 p-value versus placebo                       1
0.002                             0.015
Patients with moderate           Patients with 1mild dementia dementia (MMSE 10-17)            (MMSE 18-24)

ITT + RDO population        (n=87)             (n=44)        (n=237)            (n=115) 
Mean baseline ± SD          32.6 ± 10.4        33.7 ± 10.3   20.6 ± 7.9         20.7 ± 7.9 Mean change at 24 weeks     2.6 ± 9.4          -1.8 ± 7.2    1.9 ± 7.7          -0.2 ± 7.5 ± SD
Adjusted treatment difference                                      1                               1 4.73                            2.14 p-value versus placebo                          1
0.002                            0.010
1
1 Based on ANCOVA with treatment and country as factors and baseline ADAS-Cog as a covariate. A positive change indicates improvement.
ITT: Intent-To-Treat; RDO: Retrieved Drop Outs

Pharmacokinetic Properties

5.2 Pharmacokinetic properties

Absorption
Rivastigmine is rapidly and completely absorbed. Peak plasma concentrations are reached in approximately 1 hour. As a consequence of the rivastigmine’s interaction with its target enzyme, the increase in bioavailability is about 1.5-fold greater than that expected from the increase in dose.


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Absolute bioavailability after a 3 mg dose is about 36% 13%.. Administration of rivastigmine capsules with food delays absorption (tmax) by 90 min and lowers Cmax and increases AUC by approximately 30%.

Distribution
Protein binding of rivastigmine is approximately 40%. It readily crosses the blood brain barrier and has an apparent volume of distribution in the range of 1.8–2.7 l/kg.
Biotranformation

Rivastigmine is rapidly and extensively metabolised (half-life in plasma approximately 1 hour), primarily via cholinesterase-mediated hydrolysis to the decarbamylated metabolite. In vitro, this metabolite shows minimal inhibition of acetylcholinesterase (<10%).
Based on in vitro studies, no pharmacokinetic drug interaction is expected with medical products metabolised by the following cytochrome isoenzymes: CYP1A2, CYP2D6, CYP3A4/5, CYP2E1, CYP2C9, CYP2C8, CYP2C19, or CYP2B6. Based on evidence from animal studies, the major cytochrome P450 isoenzymes are minimally involved in rivastigmine metabolism. Total plasma clearance of rivastigmine was approximately 130 l/h after a 0.2 mg intravenous dose and decreased to 70 l/h after a 2.7 mg intravenous dose.
Elimination
Unchanged rivastigmine is not found in the urine; renal excretion of the metabolites is the major route of elimination. Following administration of 14C-rivastigmine, renal elimination was rapid and essentially complete (>90 %) within 24 hours. Less than 1% of the administered dose is excreted in the faeces.
There is no accumulation of rivastigmine or the decarbamylated metabolite in patients with Alzheimer’s Disease.

A population pharmacokinetic analysis showed that nicotine use increases the oral clearance of rivastigmine by 23% in patients with Alzheimer’s disease (n=75 smokers and 549 non- smokers) following rivastigmine oral capsule doses of up to 12 mg/day.

Special populations
Elderly
While bioavailability of rivastigmine is greater in elderly than in young healthy volunteers, studies in Alzheimer patients aged between 50 and 92 years showed no change in bioavailability with age.

Hepatic impairment
The Cmax of rivastigmine was approximately 60% higher and the AUC of rivastigmine was more than twice as high in subjects with mild to moderate hepatic impairment than in healthy subjects.

Renal impairment
Cmax and AUC of rivastigmine were more than twice as high in subjects with moderate renal impairment compared with healthy subjects; however there were no changes in Cmax and AUC of rivastigmine in subjects with severe renal impairment.