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Alzheimer's Dementia: In patients with Alzheimer's dementia participating in clinical trials, administration of single daily doses of 5 mg or 10 mg of Aricept produced steady-state inhibition of acetylcholinesterase activity (measured in erythrocyte membranes) of 63.6% and 77.3%, respectively when measured post dose. The inhibition of acetylcholinesterase (AChE) in red blood cells by donepezil hydrochloride has been shown to correlate to changes in ADAS-cog, a sensitive scale which examines selected aspects of cognition. The potential for donepezil hydrochloride to alter the course of the underlying neuropathology has not been studied. Thus, Aricept cannot be considered to have any effect on the progress of the disease.
Efficacy of treatment of Alzheimer's Dementia with Aricept has been investigated in four placebo-controlled trials, 2 trials of 6-month duration and 2 trials of 1-year duration.
In the 6 months clinical trial, an analysis was done at the conclusion of donepezil treatment using a combination of three efficacy criteria: the ADAS-Cog (a measure of cognitive performance), the Clinician Interview Based Impression of Change with Caregiver Input (a measure of global function) and the Activities of Daily Living Subscale of the Clinical Dementia Rating Scale (a measure of capabilities in community affairs, home and hobbies and personal care).
Patients who fulfilled the criteria listed as follows were considered treatment responders.
Response = Improvement of ADAS-Cog of at least 4 points.
No deterioration of CIBIC + No Deterioration of Activities of Daily Living Subscale of the Clinical Dementia Rating Scale. (See Table 1.)
Click on icon to see table/diagram/imageAricept produced a dose-dependent statistically significant increase in the percentage of patients who were judged treatment responders.
Pharmacokinetics: Absorption: Maximum plasma levels are reached approximately 3 to 4 hours after oral administration. Plasma concentrations and area under the curve rise in proportion to the dose. The terminal disposition half-life is approximately 70 hours, thus, administration of multiple single-daily doses results in gradual approach to steady-state. Approximate steady-state is achieved within 3 weeks after initiation of therapy. Once at steady-state, plasma donepezil hydrochloride concentrations and the related pharmacodynamic activity show little variability over the course of the day.
Food did not affect the absorption of donepezil hydrochloride.
Distribution: Donepezil hydrochloride is approximately 95% bound to human plasma proteins. The plasma protein binding of the active metabolite 6-O-desmethyl donepezil is not known. The distribution of donepezil hydrochloride in various body tissues has not be definitively studied. However, in a mass balance study conducted in healthy male volunteers, 240 hours after the administration of a single 5 mg dose of 14C-labeled donepezil hydrochloride, approximately 28% of the label remained unrecovered. This suggests that donepezil hydrochloride and/or its metabolites may persist in the body for more than 10 days.
Metabolism/Excretion: Donepezil hydrochloride is both excreted in the urine intact and metabolised by the cytochrome P450 system to multiple metabolites, not all of which have been identified. Following administration of a single 5 mg dose of 14C-labeled donepezil hydrochloride, plasma radioactivity, expressed as a percent of the administered dose, was present primarily as intact donepezil hydrochloride (30%), 6-O-desmethyl donepezil (11% - only metabolite that exhibits activity similar to donepezil hydrochloride), donepezil-cis-N-oxide (9%), 5-O-desmethyl donepezil (7%) and the glucuronide conjugate of 5-O-desmethyl donepezil (3%).
Approximately 57% of the total administered radioactivity was recovered from the urine (17% as unchanged donepezil), and 14.5% was recovered from the faeces, suggesting biotransformation and urinary excretion as the primary routes of elimination. There is no evidence to suggest enterohepatic recirculation of donepezil hydrochloride and/or any of its metabolites.
Plasma donepezil concentrations decline with a half-life of approximately 70 hours.
Sex, race and smoking history have no clinically significant influence on plasma concentrations of donepezil hydrochloride. The pharmacokinetics of donepezil has not been formally studied in healthy elderly subjects, or in Alzheimer's or vascular dementia patients. However, mean plasma levels in patients closely agreed with those of young healthy volunteers.
Patients with mild to moderate hepatic impairment had increased donepezil steady state concentrations; mean AUC by 48% and mean Cmax by 39% (see Dosage & Administration).
Toxicology: Preclinical safety data: Extensive testing in experimental animals has demonstrated that this compound causes few effects other than the intended pharmacological effects consistent with its action as a cholinergic stimulator (see Overdosage).
Donepezil is not mutagenic in Ames reverse mutation assay in bacteria or in the mouse lymphoma forward mutation assay in vitro. Donepezil hydrochloride did not induce unscheduled DNA synthesis in rat primary hepatocyte cultures following oral dosing of the animals.
Some clastogenic effects were observed in Chinese Hamster Lung cells in vitro, but only at concentrations approaching those overtly toxic to the cells and more than 3000 times the steady-state plasma concentrations observed in patients during clinical trials. Donepezil hydrochloride was not clastogenic in the mouse micronucleus model in vivo.
Donepezil hydrochloride had no effect on fertility in rats and was not teratogenic in rats or rabbits, but had a slight effect on stillbirths and early pup survival when administered to pregnant rats at 50 times the human dose (see Use in Pregnancy & Lactation).
