Source: Health Products Regulatory Authority (ZA) Revision Year: 2021 Publisher: Aurogen South Africa (Pty) Ltd, Woodhill Office Park, Building 1, 53 Phillip Engelbrecht Avenue, Meyersdal, Ext. 12, 1448, Johannesburg, South Africa
A 5.3 Cholinomimetics (cholinergics)
Donepezil hydrochloride is a reversible inhibitor of acetylcholinesterase, the predominant cholinesterase in the brain. Donepezil hydrochloride is over 1000 times more potent an inhibitor of this enzyme than of butylcholinesterase, an enzyme which is present mainly outside the central nervous system. In patients with Alzheimer's dementia participating in clinical trials, administration of single daily doses of 5 mg or 10 mg of donepezil 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 correspond closely to the effects in the cerebral cortex. In addition, significant correlation was demonstrated between plasma levels of donepezil hydrochloride, AChE inhibition and change in ADAS-cog, a sensitive and well validated scale which examines cognitive performance-including memory, orientation, attention, reason, language and praxis.
Current theories on the pathogenesis of the cognitive signs and symptoms of Alzheimer's disease attribute some of them to a deficiency of cholinergic neurotransmission. Donepezil hydrochloride 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 acetylcholinesterase. If this proposed mechanism of action is correct, donepezil's effect may lessen as the disease process advances and fewer cholinergic neurons remain intact. There is no evidence that donepezil alters the course of the underlying process.
The enzyme AChE also occurs peripherally in red blood cells, therefore, measurement of AChE activity in erythrocyte membranes provides an index for donepezil hydrochloride pharmacodynamics.
Oral administration of donepezil produces predictable plasma concentrations with maximal values achieved approximately 3 to 4 hours after dose 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 the 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. Neither food nor time of administration (morning versus evening dose) affect the absorption of donepezil hydrochloride.
The steady-state volume of distribution is 12 l/kg. Donepezil hydrochloride is approximately 96% bound to human plasma proteins. 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 any of its metabolites may persist in the body for more than 10 days. The average CSF:plasma ratio for both doses, expressed as a percent of the concentration in plasma, was 15,7%.
Donepezil is hepatically metabolised and the predominant route for the elimination of both the parent compound and its metabolites is renal, as 79% of the recovered dose was found in the urine with the remaining 21% in the faeces. Moreover, the parent compound, donepezil, is the predominant elimination product in urine. The major metabolites of donepezil include M1 and M2 (via O-dealkylation and hydroxylation), M11 and M12 (via glucuronidation of M1 and M2 respectively), M4 (via hydrolysis) and M6 (via N-oxidation).
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.
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