Pharmacology: Pharmacodynamics: Mechanism of Action:
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.
The effectiveness of ARICEPT Tablets 23 mg as a treatment for moderate to severe Alzheimer's disease compared to donepezil hydrochloride 10 mg has been demonstrated by the results of a randomized, double-blind, controlled clinical investigation in patients with moderate to severe Alzheimer's disease. The controlled clinical study was conducted globally in patients with probable Alzheimer's disease diagnosed by NINCDS-ADRDA and DSM-IV criteria, MMSE: range of 0-20. Patients were required to have been on a stable dose of ARICEPT 10 mg/day for at least 3 months prior to screening. One thousand four hundred and thirty four (1434) patients with moderate to severe Alzheimer's disease were randomized to 23 mg/day or 10 mg/day. The mean age of patients was 73.8 years, with a range of 47 to 90. Approximately 63% of patients were women, and 37% were men. Approximately 36% of the patients were taking memantine throughout the study.
Study Outcome Measures: The effectiveness of treatment with ARICEPT Tablets 23 mg was determined using a dual outcome assessment strategy that evaluated cognitive function using an instrument designed for more impaired patients and overall function through caregiver-rated assessment. This study showed that patients on ARICEPT Tablets 23 mg experienced important clinical benefit on both measures compared to donepezil hydrochloride 10 mg/day.
The ability of ARICEPT Tablets 23 mg to improve cognitive performance was assessed with the Severe Impairment Battery (SIB). The SIB, a multi-item instrument, has been validated for the evaluation of cognitive function in patients with moderate to severe dementia. The SIB evaluates selective aspects of cognitive performance, including elements of memory, language, orientation, attention, praxis, visuospatial ability, construction, and social interaction. The SIB scoring range is from 0 to 100, with lower scores indicating greater cognitive impairment.
The ability of ARICEPT Tablets 23 mg to produce an overall clinical effect was assessed using a Clinician's Interview-Based Impression of Change that incorporated the use of caregiver information, the CIBIC-plus. The CIBIC-plus used in this trial was a semi-structured instrument that examines four major areas of patient function: General, Cognitive, Behavioral and Activities of Daily Living. It represents the assessment of a skilled clinician based upon his/her observations at an interview with the patient, in combination with information supplied by a caregiver familiar with the behavior of the patient over the interval rated. The CIBIC-plus is scored as a seven point categorical rating, ranging from a score of 1, indicating "markedly improved," to a score of 4, indicating "no change" to a score of 7, indicating "markedly worse".
Effects on the SIB: Figure 1 shows the time course for the change from baseline in SIB score for the two treatment groups over the 24 weeks of the study. At 24 weeks of treatment, the LS mean difference in the SIB change scores for ARICEPT Tablets 23 mg treated patients compared to patients treated with 10 mg donepezil was 2.2 units (p=0.0001). ARICEPT Tablets 23 mg/day was statistically significantly superior to 10 mg/day donepezil. (See Figure 1.)
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Figure 2 illustrates the cumulative percentages of patients from each of the two treatment groups who attained the measure of improvement in SIB score shown on the X-axis. While patients assigned both to ARICEPT Tablets 23 mg and to donepezil hydrochloride 10 mg tablets have a wide range of responses, the curves show that the ARICEPT Tablets 23 mg group is more likely to show a greater improvement in cognitive performance. When such curves are shifted to the left, this indicates a greater percentage of patients responding to treatment on the SIB. (See Figure 2.)
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Effects on the CIBIC-plus: Figure 3 is a histogram of the frequency distribution of CIBIC-plus scores attained by patients at the end of 24 weeks of treatment. The mean difference between ARICEPT Tablets 23 mg and donepezil hydrochloride 10 mg tablets was 0.06 units. This difference was not statistically significant. (See Figure 3.)
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Based on population pharmacokinetic analysis of plasma donepezil concentrations measured in patients with Alzheimer's disease, following oral dosing, peak plasma concentration is achieved for ARICEPT Tablets 23 mg in approximately 8 hours, compared with 3 hours for ARICEPT 10 mg tablets. Peak plasma concentrations were almost 2-fold higher for ARICEPT 23 mg tablets than ARICEPT 10 mg tablets.
The elimination half life of donepezil is about 70 hours, and the mean apparent plasma clearance (Cl/F) is 0.13-0.19 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 12-16 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 14
C-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. Examination of the effect of CYP2D6 genotype in Alzheimer's patients showed differences in clearance values among CYP2D6 genotype subgroups. When compared to the extensive metabolizers, poor metabolizers had a 31.5% slower clearance and ultra-rapid metabolizers had a 24% faster clearance. These results suggest CYP2D6 has a minor role in the metabolism of donepezil.
In a study of 10 patients with stable alcoholic cirrhosis, the clearance of donepezil was decreased by 20% relative to 10 healthy age- and sex-matched subjects. This drug should be used with caution in patients with hepatic impairment.
In a study of 11 patients with moderate to severe renal impairment (ClC
<18 mL/min/1.73 m2
) the clearance of donepezil did not differ from 11 age- and sex-matched healthy subjects.
No formal pharmacokinetic study was conducted to examine age-related differences in the pharmacokinetics of ARICEPT Tablets 23 mg . Population pharmacokinetic analysis suggested that the clearance of donepezil in patients decreases with increasing age. When compared with 65-year old, subjects, 90-year old subjects have a 17% decrease in clearance, while 40-year old subjects have a 33% increase in clearance. The effect of age on donepezil clearance may not be clinically significant.
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 and population pharmacokinetic analysis of plasma donepezil concentrations measured in patients with Alzheimer's disease indicates that gender and race (Japanese and Caucasians) did not affect the clearance of ARICEPT to an important degree.
There was a relationship noted between body weight and clearance. Over the range of weights from 50 kg to 110 kg, clearance increased from 7.77 L/h to 14.04 L/h, with a value of 10 L/hr for 70 kg individuals.
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. Donepezil 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 donepezil to human albumin was not affected by furosemide, digoxin and warfarin.
Nonclinical toxicology: Carcinogenesis, Mutagenesis, Impairment of Fertility:
No evidence of a carcinogenic potential was obtained in an 88-week carcinogenicity study of donepezil hydrochloride conducted in CD-1 mice at doses up to 180 mg/kg/day (approximately 40 times the maximum recommended human dose of 23 mg/day on a mg/m2
basis), or in a 104-week carcinogenicity study in Sprague-Dawley rats at doses up to 30 mg/kg/day (approximately 13 times the maximum recommended human dose on a mg/m2
Donepezil was negative in a battery of genotoxicity assays (in vitro
bacterial reverse mutation, in vitro
mouse lymphoma tk, in vitro
chromosomal aberration, and in vivo
Donepezil had no effect on fertility in rats at doses up to 10 mg/kg/day (approximately 4 times the maximum recommended human dose on a mg/m2
basis) when administered to males and females prior to and during mating and continuing in females through implantation.
In a published study, female rats were given single doses of donepezil and memantine by intraperitoneal injection, each alone or in combination. When given in combination with memantine, donepezil increased the incidence and severity of memantine-induced neurodegeneration. The relevance of this finding to humans is unknown.