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. There is
no evidence that donepezil alters the course of the underlying dementing process.
Clinical Pharmacokinetics
ARICEPT® ODT is bioequivalent to ARICEPT®
Tablets. Donepezil is well absorbed with a relative oral bioavailability of 100%
and reaches peak plasma concentrations in 3 to 4 hours. Pharmacokinetics are linear
over a dose range of 1-10 mg given once daily. Neither food nor time of administration
(morning vs. evening dose) influences the rate or extent of absorption of ARICEPT®
Tablets. A food effect study has not been conducted with ARICEPT®
ODT; however, the effect of food with ARICEPT® ODT is
expected to be minimal. ARICEPT® ODT can be taken without
regard to meals.
The elimination half life of donepezil is about 70 hours and the mean apparent plasma
clearance (Cl/F) is 0.13 L/hr/kg. Following multiple dose administration, donepezil
accumulates in plasma by 4-7 fold and steady state is reached within 15 days. The
steady state volume of distribution is 12 L/kg. Donepezil is approximately 96% bound
to human plasma proteins, mainly to albumins (about 75%) and alpha1 - acid glycoprotein
(about 21%) over the concentration range of 2-1000 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 of which have been identified. Donepezil is metabolized by CYP 450 isoenzymes
2D6 and 3A4 and undergoes glucuronidation. Following 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.
Special Populations:
Hepatic Disease: In a study of 10 patients with stable alcoholic cirrhosis,
the clearance of ARICEPT® was decreased by 20% relative
to 10 healthy age and sex matched subjects.
Renal Disease: In a study of 11 patients with moderate to severe renal impairment
(ClCr < 18 mL/min/1.73 m2)
the clearance of ARICEPT® did not differ from 11 age and
sex matched healthy subjects.
Age: No formal pharmacokinetic study was conducted to examine age related
differences in the pharmacokinetics of ARICEPT®. However,
mean plasma ARICEPT® concentrations measured during therapeutic
drug monitoring of elderly patients with Alzheimer's Disease are comparable
to those observed in young healthy volunteers.
Gender and Race: No specific pharmacokinetic study was conducted to investigate
the effects of gender and race on the disposition of ARICEPT®.
However, retrospective pharmacokinetic analysis indicates that gender and race (Japanese
and Caucasians) did not affect the clearance of ARICEPT®.
Drug-Drug Interactions
Drugs Highly Bound to Plasma Proteins: Drug displacement studies have
been performed in vitro between this highly bound drug (96%) and other drugs
such as furosemide, digoxin, and warfarin. ARICEPT® at
concentrations of 0.3-10 µg/mL did not affect the binding of furosemide (5 μg/mL),
digoxin (2 ng/mL), and warfarin (3 μg/mL) to human albumin. Similarly, the binding
of ARICEPT® to human albumin was not affected by furosemide,
digoxin and warfarin.
Effect of ARICEPT® on the Metabolism of Other Drugs:
No in vivo clinical trials have investigated the effect of ARICEPT®
on the clearance of drugs metabolized by CYP 3A4 (e.g. cisapride, terfenadine) or
by CYP 2D6 (e.g. imipramine). However, in vitro studies show a low rate of
binding to these enzymes (mean Ki about 50-130 μM), that,
given the therapeutic plasma concentrations of donepezil (164 nM), indicates little
likelihood of interference.
Whether ARICEPT® has any potential for enzyme induction
is not known.
Formal pharmacokinetic studies evaluated the potential of ARICEPT®
for interaction with theophylline, cimetidine, warfarin, digoxin and ketoconazole.
No effects of ARICEPT® on the pharmacokinetics of these
drugs were observed.
Effect of Other Drugs on the Metabolism of ARICEPT®:
Ketoconazole and quinidine, inhibitors of CYP450, 3A4 and 2D6, respectively, inhibit
donepezil metabolism in vitro. Whether there is a clinical effect of quinidine
is not known. In a 7-day crossover study in 18 healthy volunteers, ketoconazole
(200mg q.d.) increased mean donepezil (5mg q.d.) concentrations (AUC0-24
and Cmax) by 36%. The clinical relevance of this increase
in concentration is unknown.
Inducers of CYP 2D6 and CYP 3A4 (e.g., phenytoin, carbamazepine, dexamethasone,
rifampin, and phenobarbital) could increase the rate of elimination of ARICEPT®.
Formal pharmacokinetic studies demonstrated that the metabolism of ARICEPT®
is not significantly affected by concurrent administration of digoxin or cimetidine.