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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 action for rivastigmine 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, the effect of rivastigmine 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.

Pharmacodynamics

After a 6-mg oral dose of rivastigmine in humans, 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.

Pharmacokinetics

Absorption

After the first dose, there is a lag time of 0.5-1 hour in the absorption of rivastigmine from Exelon Patch (rivastigmine transdermal system). Concentrations then rise slowly typically reaching a maximum after 8 hours, although maximum values (Cmax) are often reached at later times as well (10-16 hours). After the peak, plasma concentrations slowly decrease over the remainder of the 24-hour period of application. At steady state, trough levels are approximately 60-80% of peak levels. Fluctuation (between Cmax and Cmin) is lower for Exelon Patch (rivastigmine transdermal system) than for the oral formulation. Exelon Patch (rivastigmine transdermal system) 9.5 mg/24 hours exhibited exposure approximately the same as that provided by an oral dose of 6 mg twice daily (i.e., 12 mg/day).

Figure 2: Rivastigmine Plasma Concentrations Following Dermal 24-Hour Patch Application

Inter-subject variability in exposure was lower (43-49%) for the Exelon Patch (rivastigmine transdermal system) formulation as compared with the oral formulations (73-103%).

A relationship between drug exposure at steady state (rivastigmine and metabolite NAP226-90) and body weight was observed in Alzheimer's dementia patients. Compared to a patient with a body weight of 65 kg, the rivastigmine steady-state concentrations in a patient with a body weight of 35 kg are approximately doubled, while for a patient with a body weight of 100 kg the concentrations are approximately halved. The effect of body weight on drug exposure suggests special attention to patients with very low body weight during up-titration [see DOSAGE AND ADMINISTRATION].

Over a 24-hour dermal application, approximately 50% of the drug load is released from the system.

Exposure (AUC∞) to rivastigmine (and metabolite NAP266-90) was highest when the patch was applied to the upper back, chest, or upper arm. Two other sites (abdomen and thigh) could be used if none of the three other sites is available, but the practitioner should keep in mind that the rivastigmine plasma exposure associated with these sites was approximately 20-30% lower.

There was no relevant accumulation of rivastigmine or the metabolite NAP226-90 in plasma in patients with Alzheimer's disease upon multiple dosing.

Distribution

Rivastigmine is weakly bound to plasma proteins (approximately 40%) over the therapeutic range. It readily crosses the blood-brain barrier, reaching CSF peak concentrations in 1.4-2.6 hours. It has an apparent volume of distribution in the range of 1.8-2.7 L/kg.

Metabolism

Rivastigmine is extensively metabolized primarily via cholinesterase-mediated hydrolysis to the decarbamylated metabolite NAP226-90. In vitro, this metabolite shows minimal inhibition of acetylcholinesterase ( < 10%). Based on evidence from in-vitro and animal studies, the major cytochrome P450 isoenzymes are minimally involved in rivastigmine metabolism.

The metabolite-to-parent AUC∞ ratio was about 0.7 after Exelon Patch (rivastigmine transdermal system) application versus 3.5 after oral administration, indicating that much less metabolism occurred after dermal treatment. Less NAP226-90 is formed following patch application, presumably because of the lack of presystemic (hepatic first pass) metabolism. Based on in-vitro studies, no unique metabolic routes were detected in human skin.

Elimination

Renal excretion of the metabolites is the major route of elimination. Unchanged rivastigmine is found in trace amounts in the urine. 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 feces. The apparent elimination half-life in plasma is approximately 3 hours after patch removal. Renal clearance was approximately 2.1-2.8 L/hr.

Clinical Studies

The effectiveness of the Exelon Patch (rivastigmine transdermal system) in Alzheimer's disease and dementia associated with Parkinson's disease was based on the results of a single controlled trial in patients with

Alzheimer's disease (see below) as well as on three controlled trials of the immediate-release capsule in Alzheimer's disease and one controlled trial in dementia associated with Parkinson's disease (see package insert for the Exelon capsules and oral solution for details).

International 24-Week Study of Exelon Patch (rivastigmine transdermal system)

This was a randomized double-blind clinical investigation in patients with Alzheimer's disease [diagnosed by NINCDS-ADRDA and DSM-IV criteria, Mini-Mental Status Examination (MMSE) score ≥ 10 and ≤ 20]. The mean age of patients participating in this trial was 74 years with a range of 50-90 years. Approximately 67% of patients were women and 33% were men. The racial distribution was Caucasian 75%, Black 1%, Oriental 9% and Other Races 15%.

Study Outcome Measures

The effectiveness of the Exelon Patch (rivastigmine transdermal system) was evaluated in this study using a dual outcome assessment strategy.

The ability of the Exelon Patch (rivastigmine transdermal system) 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 0-70, 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 ability of the Exelon Patch (rivastigmine transdermal system) to produce an overall clinical effect was assessed using the Alzheimer's Disease Cooperative Study - Clinical Global Impression of Change (ADCS-CGIC). The ADCS-CGIC is a more standardized form of CIBIC-Plus and is also 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”.

Study Results

In this study, 1195 patients were randomized to one of the following 4 treatments: Exelon Patch (rivastigmine transdermal system) 9.5 mg/24 hours, Exelon Patch (rivastigmine transdermal system) 17.4 mg/24 hours, Exelon capsules in a dose of 6 mg BID, or placebo. This 24-week study was divided into a 16-week titration phase followed by an 8-week maintenance phase. In the active treatment arms of this study, doses below the target dose were permitted during the maintenance phase in the event of poor tolerability.

Effects on the ADAS-Cog

Figure 3 illustrates the time course for the change from baseline in ADAS-Cog scores for all 4 treatment groups over the 24-week study. At 24 weeks, the mean differences in the ADAS-Cog change scores for the Exelontreated patients, compared to the patients on placebo, were 1.8, 2.9, and 1.8 units for the Exelon Patch (rivastigmine transdermal system) 9.5 mg/24 hours, Exelon Patch (rivastigmine transdermal system) 17.4 mg/24 hours, and Exelon capsule 6 mg BID groups, respectively. The difference between each of these groups and placebo was statistically significant.

Effects on the ADCS-CGIC

Figure 4 is a histogram of the distribution of patients' scores on the ADCS-CGIC for all 4 treatment groups.

At 24 weeks, the mean difference in the ADCS-CGIC scores for the comparison of patients in each of the Exelontreated groups with the patients on placebo was 0.2 units. The difference between each of these groups and placebo was statistically significant.

Figure 3: Time Course of the Change from Baseline in ADAS-Cog Score for Patients Observed at Each Time Point

Figure 4: Distribution of ADCS-CGIC Scores for Patients Completing the Study

Last reviewed on RxList: 9/17/2010
This monograph has been modified to include the generic and brand name in many instances.