CLINICAL PHARMACOLOGY

Current theory 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 functionally intact. There is no evidence that donepezil alters the course of the underlying dementing process.

Clinical Trial Data

The effectiveness of ARICEPT™ as a treatment for Alzheimer’s Disease is demonstrated by the results of two randomized, double-blind, placebo-controlled clinical investigations in patients with Alzheimer’s Disease (diagnosed by NINCDS and DSM III-R criteria, Mini-Mental State Examination ³10 and £26 and Clinical Dementia Rating of 1 or 2). The mean age of patients participating in ARICEPT™ trials was 73 years with a range of 50 to 94. Approximately 62% of patients were women and 38% were men. The racial distribution was white 95%, black 3% and other races 2%.

Study Outcome Measures: In each study the effectiveness of treatment with ARICEPT™ was evaluated using a dual outcome assessment strategy.

The ability ofARICEPT™ to improve cognitive performance was assessed with the cognitive subscale of the Alzheimer’s Disease Assessment Scale (ADAS-cog), a multi-tem instrument that has been extensively validated in longitudinal cohorts of Alzheimer’s Disease patients. The ADAS-cog examines selected aspects of cognitive performance including elements of memory, orientation, attention, reasoning, language and praxis. The ADAS-cog scoring range is from 0 to 70, with higher scores indicating greater cognitive impairment. Elderly normal adults may score as low as 0 or 1, but it is not unusual for non-demented adults to score slightly higher.

The patients recruited as participants in each study had mean scores on the Alzheimer’s Disease Assessment Scale (ADAS-cog) of approximately 26 units, with a range from 4 to 61. Experience gained in longitudinal studies of ambulatory patients with mild to moderate Alzheimer’s Disease suggest that they gain 6 to 12 units a year on the ADAS-cog. However, lesser degrees of change are seen in patients with very mild or very advanced disease because the ADAS-cog is not uniformly sensitive to change over the course of the disease. The annualized rate of decline in the placebo patients participating in ARICEPT™ trials was approximately 2 to 4 units per year.

The ability of ARICEPT™ to produce an overall clinical effect was assessed using a Clinician’s Interview Based Impression of Change that required the use of caregiver information, the CIBIC plus. The CIBIC plus is not a single instrument and is not a standardized instrument like the ADAS-cog. Clinical trials for investigational drugs have used a variety of CIBIC formats, each different in terms of depth and structure. As such, results from a CIBIC plus reflect clinical experience from the trial or trials in which it was used and can not be compared directly with the results of CIBIC plus evaluations from other clinical trials. The CIBIC plus used in ARICEPT™ trials was a semi-structured instrument that was intended to examine 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." The CIBIC plus has not been systematically compared directly to assessments not using informative from caregivers (CIBIC) or other global methods.

Thirty-Week Study

In a study of 30 weeks duration, 473 patients were randomized to receive single daily doses of placebo, 5 mg/day or 10 mg/day of ARICEPT™. The 30-week study was divided into a 24-week double-blind active treatment phase followed by a 6-week single-blind placebo washout period. The study was designed to compare 5 mg/day or 10 mg/day fixed doses of ARICEPT™ to placebo. However, to reduce the likelihood of cholinergic effects, the 10 mg/day treatment was started following an initial 7-day treatment with 5 rng/day doses.

Effects on the ADAS-cog: Time-course of the change from baseline in ADAS-cog score for patients completing 24 weeks of treatment: After 24 weeks of treatment, the mean differences in the ADAS-cog change scores for ARICEPT™ treated patients compared to the patients on placebo were 2.8 and 3.1 units for the 5 mg/day and 10 mg/day treatments, respectively. These differences were statistically significant. While the treatment effect size may appear to be slightly greater for the 10 mg/day treatment, there was no statistically significant difference between the two active treatments.

Following 6 weeks of placebo washout, scores on the ADAS-cog for both the ARICEPT™ treatment groups were indistinguishable from those patients who had received only placebo for 30 weeks. This suggests that the beneficial effects of ARICEPT™ abate over 6 weeks following discontinuation of treatment and do not represent a change in the underlying disease. There was no evidence of a rebound effect 6 weeks after abrupt discontinuation of therapy.

Cumulative percentage of patients completing 24 weeks of double-blind treatment with specified changes from baseline ADAS-cog scores (the percentages of randomized patients who completed the study were: placebo 80%, 5 mg/day 85%, and 10 mg/day 68%): Both patients assigned to placebo and ARICEPT™ had a wide range of responses, but the active treatment groups were more likely to show the greater improvements.

Effects on the CIBIC plus: CIBIC plus scores attained by patients assigned to each of the three treatment groups who completed 24 weeks of treatment: The mean drug-placebo differences for these groups of patients were 0.35 units and 0.39 units for 5 mg/day and 10 mg/day of ARICEPT™, respectively. These differences were statistically significant. There was no statistically significant difference between the two active treatments.

Fifteen-Week Study

In a study of 15 weeks duration, patients were randomized to receive single daily doses of placebo or either 5 mg/day or 10 mg/day of ARICEPT™ for 12 weeks, followed by a 3-week placebo washout period. As in the 30-week study, to avoid acute cholinergic effects, the 10 mg/day treatment followed an initial 7-day treatment with 5 mg/day doses.

Effects on the ADAS-cog: Time-course of the change from baseline in ADAS-cog score for patients completing the 15 week study: After 12 weeks of treatment, the differences in mean ADAS-cog change scores for the ARICEPT™ treated patients compared to the patients on placebo were 2.7 and 3.0 units each, for the 5 and 10 mg/day ARICEPT™ treatment groups, respectively. These differences were statistically significant. The effect size for the 10 mg/day group may appear to be slightly larger than that for 5 mg/day. However, the differences between active treatments were not statistically significant.

Following 3 weeks of placebo washout, scores on the ADAS-cog for both the ARICEPT™ treatment groups increased, indicating that discontinuation of ARICEPT™ resulted in a loss of its treatment effect. The duration of this placebo washout period was not sufficient to characterize the rate of loss of the treatment effect, but, the 30-week study demonstrated that treatment effects associated with the use of ARICEPT™ abate within 6 weeks of treatment discontinuation.

Cumulative percentages of patients with specified changes from Baseline ADAS-cog scores (the percentages of randomized patients within each treatment group who completed the study were: placebo 93%, 5 mg/day 90% and 10 mg/day 82%): As observed in the 30-week study, patients assigned to either placebo or to ARICEPT™ have a wide range of responses, but the ARICEPT™ treated patients are more likely to show the greater improvements in cognitive performance.

Effects on the CIBIC plus: Frequency distribution of CIBIC plus scores at week 12: The differences in mean scores for ARICEPT™ treated patients compared to the patients on placebo at week12 were 0.36and 0.38 units for the 5 mg/day and 10 mg/day treatment groups, respectively. These differences were statistically significant. In both studies, patient age, sex and race were not found to predict the clinical outcome of ARICEPT™ treatment.

Clinical Pharmacokinetics

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 l-10 mg given once daily. Neither food nor time of administration (morning vs. evening dose) influences the rate or extent of absorption. 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 alpha-acid glycoprotein (about 2l%) over the concentration range of 2-1000 mg/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 206 and 3A4 and undergoes glucuronidation. Following administration of W-labeled donepezil, plasma- radioactivity expressed as a percent of the administered dose, was present primarily as intact donepezil (53%) and as 6-0-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 26% 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 4 patients with moderate to severe renal impairment (Cl, <22 mL/min/1.73m2) the clearance of ARICEPT™ did not differ from 4 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 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 mcg/mL did not affect the binding of furosemide (5 mcg/mL), digoxin (2 mg/mL), and warfarin (3 mc/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 K, about 50130 mcM), that, given the therapeutic plasma concentrations of donepezil (l64 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 and digoxin. No significant effects 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 these inhibitors is not known. 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.