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Pharmacotherapeutic Group: Cholinesterase Inhibitor.
Pharmacology: Pharmacodynamics: Alzheimer's disease has been shown to be associated with a relative decrease in cholinergic system activity in the cerebral cortex and other areas of the brain.
Donepezil hydrochloride is a specific and reversible inhibitor of acetylcholinesterase (AChE), the predominant cholinesterase in the brain. It exerts its therapeutic effect by enhancing cholinergic function in the central nervous system by increasing the concentration of acetylcholine through reversible inhibition of its hydrolysis by AChE.
In vitro studies show that the inhibitory activity of donepezil was over 1000 times more potent over AChE than that of butylcholinesterase, an enzyme which is present mainly outside the central nervous system.
There is no evidence that donepezil alters the course of the underlying dementing process.
Pharmacokinetics: Donepezil hydrochloride is well absorbed with a relative oral bioavailability of 100%. It reaches peak plasma concentrations in 3-4 hours. Oral administration of donepezil produces highly predictable plasma concentrations; plasma concentrations and area under the curve (AUC) rise in proportion to the dose. Neither food nor time of administration (morning vs evening dose) influences the rate or extent of donepezil hydrochloride absorption.
Following multiple dose administration, donepezil accumulates in plasma by 4-7 fold, and steady state is reached within 15 days. Once at steady-state, plasma donepezil hydrochloride concentrations and the related pharmacodynamic activity show little variability over the course of the day.
A randomized, open-label, single-dose, two-way cross-over study, involving 28 healthy adult subjects (18-55 years old), was done to compare the bioavailability, characterize the pharmacokinetic profile and assess bioequivalence of the test formulation, Dopezil 5 mg tablet, and 5 mg tablet of a reference standard. The results showed that 90% CI for maximum plasma concentration (Cmax), AUC0-t and AUC0-inf are within the predefined bioequivalence limits of 80 to 125%.
Donepezil's steady state volume of distribution is 12 L/kg. It is approximately 96% bound to human plasma proteins, mainly to albumins (about 75%) and alpha1-acid glycoprotein (about 21%) over the concentration range of 2-1,000 ng/mL.
Donepezil is both excreted in the urine intact and extensively metabolized to four major metabolites, two of which are known to be active, and a number of minor metabolites, not all have been identified. Donepezil is metabolized by the CYP450 isoenzymes 2D6 and 3A4 and undergoes glucuronidation. The rate of metabolism of donepezil is slow and does not appear to be saturable.
After administration of 14C-labeled donepezil, plasma radioactivity, expressed as a percent of the administered dose, was present primarily as intact donepezil (53%) and as 6-O-desmethyl donepezil (11%), which has been reported to inhibit AChE to the same extent as donepezil in vitro and was found in plasma at concentrations equal to about 20% of donepezil. Approximately 57% and 15% of the total radioactivity was recovered in urine and feces, respectively, over a period of 10 days, while 28% remained unrecovered, with about 17% of the donepezil dose recovered in the urine as unchanged drug. Evidence on enterohepatic recirculation of donepezil and/or any of its metabolites has not been established.
The elimination half-life of donepezil is about 70 hours, and the mean apparent plasma clearance (Cl/F) is 0.13 L/hr/kg. Plasma donepezil concentrations decline with a half-life of approximately 70 hours.
Special Populations: Renal Impairment: A study of patients with moderate to severe renal impairment (Cl < 18 mL/min/1.73 m2) showed that donepezil clearance did not differ from age- and sex-matched healthy subjects.
Hepatic Impairment: A study of patients with stable alcoholic cirrhosis showed that donepezil clearance was decreased by 20% relative to healthy age- and sex-matched subjects.
Elderly: Donepezil's mean plasma concentrations measured during therapeutic drug monitoring of elderly patients with Alzheimer's disease are comparable to those observed in young healthy volunteers.
