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Brain-selective cholinesterase inhibitor.
Pharmacology: Pathological changes in Alzheimer's disease involve cholinergic neuronal pathways that project from the basal forebrain to the cerebral cortex and hippocampus. These pathways are known to be involved in attention, learning and memory and other cognitive processes. Rivastigmine, a brain-selective acetylcholinesterase inhibitor of the carbamate type, is thought to facilitate cholinergic neurotransmission by slowing the degradation of acetylcholine released by functionally intact cholinergic neurons. Data from animal studies indicate that rivastigmine selectively increases the availability of acetylcholine in the cortex and hippocampus. Thus, Exelon may have an ameliorative effect on cholinergic-mediated cognitive deficits associated with Alzheimer's disease. In addition, there is some evidence that cholinesterase inhibition could slow the formation of amyloidogenic β-amyloid-precursor protein (APP) fragments, and thus of amyloid plaques, which are one of the main pathological features of Alzheimer's disease.
Rivastigmine interacts with its target enzyme by forming a covalently bound complex that temporarily inactivates the enzyme. In man, an oral 3-mg dose decreases acetylcholinesterase activity in CSF by approximately 40% within the first 1.5 hrs after administration. Activity of the enzyme returns to baseline levels about 9 hrs after the maximum inhibitory effect has been achieved. In patients with Alzheimer's disease, inhibition of acetylcholinesterase in CSF by rivastigmine was dose-dependent up to 6 mg given twice daily, the highest dose tested.
Clinical Studies: The efficacy of Exelon in the treatment of Alzheimer's disease has been demonstrated in placebo-controlled studies. Results from 2 pivotal 26-week multicentre studies comparing 1-4 mg/day and 6-12 mg/day with placebo, as well as pooled analysis of phase III studies have established that Exelon produces significant improvement in the major domains of cognition, global functioning and activities of daily living, and in disease severity. Both the low and high dose ranges showed benefit for cognition, global functioning and disease severity; in addition, the higher dose range produced benefit in activities of daily living.
The following key outcome measures were used in these studies: Alzheimer's Disease Assessment Scale (ADAS-Cog): A performance-based test system that measures cognitive areas relevant for patients with Alzheimer's disease eg, attention, learning, memory and language.
Clinician Interview-Based Impression of Change-Plus (CIBIC-Plus): A clinician-rated assessment of the patient's global change in the domains of cognition, behavior and functioning, incorporating separate patient and caregiver inputs.
Progressive Deterioration Scale (PDS): A caregiver-rated evaluation of the patient's ability to perform activities of daily living eg, toileting, washing, eating and helping with household chores and shopping.
Study results have indicated that onset of efficacy is generally as early as week 12 and is maintained at the end of 6 months of treatment. Patients treated with 6-12 mg experienced improvement in cognition, activities of daily living and global functioning, while placebo patients showed deterioration. The effects of Exelon on these measures (eg, ADAS-Cog difference from placebo 5 points at week 26) indicate a delay in the rate of deterioration of at least 6 months.
Analyses performed to detect those subtests and symptoms of the ADAS-Cog and CIBIC-Plus, respectively, which improved in patients treated with Exelon indicated that ADAS-Cog subtests (ideational praxis, orientation, test instructions, word recall, language ability and word recognition) were significantly improved at week 26 with Exelon 6-12 mg.
Pharmacokinetics: Absorption: Rivastigmine is rapidly and completely absorbed. Peak plasma concentrations are reached in approximately 1 hr. As a consequence of the drug's interaction with its target enzyme, the increase in bioavailability is about 1.5-fold greater than that expected from the increase in dose. Absolute bioavailability after a 3-mg dose is about 36%. Administration of rivastigmine with food delays absorption (tmax) by 90 min and lowers Cmax and increases AUC by approximately 30%.
Distribution: Rivastigmine is weakly bound to plasma proteins (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.
Metabolism: Rivastigmine is rapidly and extensively metabolized (half-life in plasma approximately 1 hr), primarily via cholinesterase-mediated hydrolysis to the decarbamylated metabolite. In vitro, this metabolite shows minimal inhibition of acetylcholinesterase (<10%). Based on evidence from in vitro and animal studies, the major cytochrome P-450 isoenzymes are minimally involved in rivastigmine metabolism. Consistent with these observations is the finding that no drug interactions relating to cytochrome P-450 have been observed in humans (see Interactions).
Excretion: 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 hrs. Less than 1% of the administered dose is excreted in the feces. There is no accumulation of rivastigmine or the decarbamylated metabolite in patients with Alzheimer's disease.
Elderly Subjects: While bioavailability of rivastigmine is greater in elderly than in young healthy volunteers, studies in Alzheimer patients between 50 and 92 years showed no change in bioavailability with age.
