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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 (see above) demonstrated that treatment effects associated with the use of ARICEPT® abate within 6 weeks of treatment discontinuation. Figure 5 illustrates the cumulative percentages of patients from each of the three treatment groups who attained the measure of improvement in ADAS-cog score shown on the X axis. The same three change scores, (7-point and 4-point reductions from baseline or no change in score) as selected for the 30-week study have been used for this illustration. The percentages of patients achieving those results are shown in the inset table. As observed in the 30-week study, the curves demonstrate that patients assigned to either placebo or to ARICEPT® have a wide range of responses, but that the ARICEPT® treated patients are more likely to show the greater improvements in cognitive performance. Text Continues Below
Effects on the CIBIC plus: Figure 6 is a histogram of the frequency distribution of CIBIC plus scores attained by patients assigned to each of the three treatment groups who completed 12 weeks of treatment. The differences in mean scores for ARICEPT® treated patients compared to the patients on placebo at Week 12 were 0.36 and 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 1-10 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 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 11 patients with stable alcoholic cirrhosis, the clearance of ARICEPT® was decreased by 20% relative to 11 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®.
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