Pharmacotherapeutic group: Cholinesterase inhibitors.
Pharmacology: Pharmacodynamics: Donepezil hydrochloride is a selective and reversible inhibitor of acetylcholinesterase, the predominant cholinesterase in the brain. Donepezil hydrochloride is, in vitro over 1000 times more potent, an inhibitor of this enzyme than of butyrylcholinesterase, an enzyme that is present mainly outside the central nervous system.
Clinical studies: Mild and moderate Alzheimer's disease: In patients with Alzheimer's Dementia participating in clinical trials, administration of single daily doses of 5 mg or 10 mg of donepezil hydrochloride 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 that examines selected aspects of cognition. The potential for donepezil hydrochloride to alter the course of the underlying neuropathology has not been studied. Thus, donepezil hydrochloride can not be considered to have any effect on the progress of the disease.
Efficacy of treatment of Alzheimer's Dementia with donepezil 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.
In this analysis, a combination of three efficacy criteria has been used. The ADAS-Cog (a measure of cognitive performance), the Clinician Interview Based Impression of Change with Caregiver Input (CIBIC+ - a measure of global function) and the Activities of Daily Living Subscale of the Clinical Dementia Rating Scale (CDR - a measure of capabilities in community affairs, home and hobbies and personal care).
Pharmacokinetics: Absorption: Maximum plasma levels (Cmax) are reached approximately 3 to 4 hours after oral administration. Plasma concentrations and area under the curve (AUC) 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 does 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-desmethyldonepezil is not known.
The distribution of donepezil hydrochloride in various body tissues has not been 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-labelled 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.
Biotransformation: 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-labelled donepezil hydrochloride, plasma radioactivity, expressed as a percent of the administered dose, was present primarily as intact donepezil hydrochloride (30%), 6-O-desmethyldonepezil (11% - only metabolite that exhibits activity similar to donepezil hydrochloride), donepezil-cis-N-oxide (9%), 5-O-desmethyldonepezil (7%) and the glucuronide conjugate of 5-O-desmethyldonepezil (3%).
Elimination: Its plasma half life is approximately 70 hours. 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.