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Author Report for: Rogers SL

Title: The effects of donepezil in Alzheimer's disease - results from a multinational trial
Burns A, Rossor M, Hecker J, Gauthier S, Petit H, Moller HJ, Rogers SL, Friedhoff LT
Ref: Dementia & Geriatric Cognitive Disorders, 10:237, 1999 : PubMed
Abstract


ESTHER: Burns_1999_Dement.Geriatr.Cogn.Disord_10_237
PubMedSearch: Burns 1999 Dement.Geriatr.Cogn.Disord 10 237
PubMedID: 10325453

Abstract

Donepezil has been shown to be well tolerated and to improve cognition and global function in patients with mild to moderately severe Alzheimer's disease (AD). The current trial was undertaken to investigate further the efficacy and safety of donepezil, in a multinational setting, in patients with mild to moderately severe AD. This 30-week, placebo-controlled, parallel-group study consisted of a 24-week, double-blind treatment phase followed by a 6-week, single-blind, placebo washout. Eight hundred and eighteen patients with mild to moderately severe AD were randomly allocated to treatment with single, daily doses of 5 or 10 mg donepezil, or placebo. The two primary efficacy measures were: a cognitive performance test, the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog) and a global evaluation, the Clinician's Interview-Based Impression of Change with caregiver input (CIBIC plus). Secondary outcome measures included the Sum of the Boxes of the Clinical Dementia Rating Scale (CDR-SB), a modified Interview for Deterioration in Daily living activities in Dementia (IDDD) and a patient rated quality of life assessment. Statistically significant improvements in cognitive and global function were observed, as evaluated by ADAS-cog and CIBIC plus, respectively, in both the 5 and 10 mg/day donepezil groups, compared with placebo. Treatment-associated changes were also observed in functional skills, as shown by improved scores on the CDR-SB and the complex-tasks component of the IDDD. A dose-response effect was evident, with the 10 mg/day donepezil group demonstrating greater benefits in all outcome measures than the 5 mg/day group. Donepezil was well tolerated by this patient population and did not produce any clinically significant laboratory test abnormalities. The results of this study confirm that donepezil is effective and well tolerated in treating the symptoms of mild to moderately severe AD.



        

Title: Pharmacokinetic and pharmacodynamic profile of donepezil HCl following multiple oral doses
Rogers SL, Cooper NM, Sukovaty R, Pederson JE, Lee JN, Friedhoff LT
Ref: British Journal of Clinical Pharmacology, 46 Suppl 1:7, 1998 : PubMed
Abstract


ESTHER: Rogers_1998_Br.J.Clin.Pharmacol_46 Suppl 1_7
PubMedSearch: Rogers 1998 Br.J.Clin.Pharmacol 46 Suppl 1 7
PubMedID: 9839759

Abstract

AIM: The aim of this study was to characterize the pharmacokinetics and pharmacodynamics of donepezil HCl, a new, chemically distinct and specific acetylcholinesterase (AChE) inhibitor for the treatment of Alzheimer's disease, following multiple-dose administration.
METHODS: This was a double-blind, randomized, placebo-controlled, multiple-dose study in healthy male volunteers (n=27). Three dose levels were investigated in sequential order: 1, 3 and 5 mg. Each dose was administered orally, once a day, for 21 consecutive days. Donepezil concentrations in plasma were quantified by HPLC. Pharmacodynamic activity was determined by the radioenzymatic measurement of erythrocyte membrane acetylcholinesterase (rbc-AChE) inhibition.
RESULTS: The pharmacokinetic disposition of donepezil was observed to be dose proportional. The mean terminal disposition half-life was 79.5+/-19.0 h which resulted in a slow approach to steady state (14-21 days). A four- to sixfold increase in donepezil plasma concentration was observed during this time; however, no further increase was evident after achievement of steady state. The mean donepezil plasma concentration at steady state (Css) was 14.2 ng ml(-1). Neither the rate of accumulation nor the rate of clearance was dose dependent. Inhibition of rbc-AChE was directly correlated with donepezil concentration over a wide concentration range, with the higher concentrations showing the expected hyperbolic relationship. Donepezil was well tolerated by all subjects with no clinically significant changes in laboratory or physical parameters observed at any dose.
CONCLUSIONS: The pharmacokinetics of donepezil were found to be dose proportional following the administration of multiple doses to healthy volunteers. A predictable relationship was also observed between plasma donepezil concentrations and rbc-AChE inhibition. The half-life of donepezil makes it suitable for once-daily dosing.



        

Title: Donepezil improves cognition and global function in Alzheimer disease: a 15-week, double-blind, placebo-controlled study. Donepezil Study Group
Rogers SL, Doody RS, Mohs RC, Friedhoff LT
Ref: Archives of Internal Medicine, 158:1021, 1998 : PubMed
Abstract


ESTHER: Rogers_1998_Arch.Intern.Med_158_1021
PubMedSearch: Rogers 1998 Arch.Intern.Med 158 1021
PubMedID: 9588436
Inhibitor(s) related to this paper: Aricept~Donepezil~E2020

Abstract

BACKGROUND: Donepezil hydrochloride (Aricept) is a selective acetylcholinesterase inhibitor developed for the treatment of Alzheimer disease. This phase 3 study was 1 of 2 pivotal trials undertaken to establish the efficacy and safety of using donepezil in patients with mild to moderately severe Alzheimer disease. OBJECTIVES: To further examine the efficacy and safety of using donepezil in the treatment of patients with mild to moderately severe Alzheimer disease. To examine the relationships between plasma donepezil concentrations, inhibition of red blood cell acetylcholinesterase activity, and clinical response.
METHODS: This was a 12-week, double-blind, placebo-controlled, parallel-group trial with a 3-week single-blind washout. Outpatients at 23 centers in the United States were randomized to receive placebo, 5 mg of donepezil hydrochloride, or 10 mg of donepezil hydrochloride (5 mg/d during week 1 then 10 mg/d thereafter) administered once daily at bedtime. Primary efficacy was measured using the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-cog) and Clinician's Interview-Based Impression of Change including caregiver information (CIBIC plus).
RESULTS: A total of 468 patients entered the study, more than 97% of whom were included in the intention-to-treat (end point) analyses. The use of donepezil produced statistically significant improvements in ADAS-cog, CIBIC plus, and Mini-Mental State Examination scores, relative to placebo. The mean drug-placebo differences, at end point, for the groups receiving 5 mg/d and 10 mg/d of donepezil hydrochloride were, respectively, 2.5 and 3.1 units for ADAS-cog (P<.001); 0.3 and 0.4 units for CIBIC plus (P< or =.008); and 1.0 and 1.3 units for Mini-Mental State Examination (P< or =.004). On the CIBIC plus scale, 32% and 38% of patients, respectively, treated with 5 mg/d and 10 mg/d of donepezil hydrochloride demonstrated clinical improvement (a score of 1, 2, or 3) compared with placebo (18%). The mean (+/-SEM) donepezil plasma concentrations at study end point were 25.9 +/- 0.7 ng/mL and 50.6 +/- 1.9 ng/mL in the groups receiving dosages of 5 mg/d and 10 mg/d, respectively. Corresponding mean (+/-SEM) percentages of inhibition of red blood cell acetylcholinesterase activity were 63.9% +/- 0.9% and 74.7% +/- 1.2% for these 2 dosages, respectively. There was a statistically significant positive correlation between plasma concentrations of donepezil and acetylcholinesterase inhibition; the EC50 (50% effect) was obtained at a concentration of 15.6 ng/mL. A plateau of inhibition (80%-90%) was reached at plasma donepezil concentrations higher than 50 ng/mL. The correlations between plasma drug concentrations and both ADAS-cog (P<.001) and CIBIC plus (P = .006) were also statistically significant, as were the correlations between red blood cell acetylcholinesterase inhibition and change in ADAS-cog (P<.001) and CIBIC plus (P = .005). The incidence of treatment-emergent adverse events with both dosages of donepezil (68%-78%) was comparable with that observed with placebo (69%). The use of 10 mg/d of donepezil hydrochloride was associated with transient mild nausea, insomnia, and diarrhea. There were no treatment-emergent clinically significant changes in vital signs or clinical laboratory test results. More important, the use of donepezil was not associated with the hepatotoxic effects observed with acridine-based cholinesterase inhibitors. CONCLUSION: Donepezil hydrochloride (5 and 10 mg) administered once daily is a well-tolerated and efficacious agent for treating the symptoms of mild to moderately severe Alzheimer disease.



        

Title: Pharmacokinetic and pharmacodynamic profile of donepezil HCl following single oral doses
Rogers SL, Friedhoff LT
Ref: British Journal of Clinical Pharmacology, 46 Suppl 1:1, 1998 : PubMed
Abstract


ESTHER: Rogers_1998_Br.J.Clin.Pharmacol_46 Suppl 1_1
PubMedSearch: Rogers 1998 Br.J.Clin.Pharmacol 46 Suppl 1 1
PubMedID: 9839758

Abstract

AIM: The aim of this study was to characterize the pharmacokinetic and pharmacodynamic profile of donepezil HCl, a chemically distinct and specific acetylcholinesterase (AChE) inhibitor for the treatment of Alzheimer's disease, following administration of single oral doses.
METHODS: This was a double-blind, randomized, single-dose, placebo-controlled, sequential-group, ascending-dose study in healthy male volunteers (n = 48). Six dose levels were investigated, ranging from 0.3 to 6.0 mg. Donepezil concentrations in plasma were determined by HPLC with UV detection. Pharmacodynamic activity was determined by the radioenzymatic measurement of erythrocyte membrane acetylcholinesterase (rbc-AChE) inhibition.
RESULTS: The pharmacokinetic disposition of donepezil was observed to be both linear and dose proportional following single-dose administration. The mean peak plasma concentration (Cmax) of donepezil was observed at 4.1+/-1.5 h. The mean terminal disposition half-life was 81.5+/-22.0 h. The post-absorption phase of the plasma concentration-time curves for the 4.0 mg and 6.0 mg doses appeared to be biphasic, but the rate of donepezil clearance was independent of dose. Plasma concentrations for the 0.3, 0.6 and 0.9 mg dose groups were generally below the level of HPLC detection (2.0 ng ml(-1)), preventing accurate characterization of these doses. A direct correlation was observed between plasma donepezil concentrations and extent of AChE inhibition. For the 4.0 and 6.0 mg donepezil dose groups, maximal AChE inhibition (Emax) ranged from 33% to 35% and there was significant correlation between AChE inhibition and donepezil plasma concentration (P<0.005).
CONCLUSIONS: The pharmacokinetics of donepezil were found to be linear and dose proportional following the administration of single doses to healthy volunteers. A direct correlation was also observed between plasma donepezil concentrations and AChE inhibition. The extended half-life of donepezil makes it suitable for once-daily dosing.



        

Title: A 24-week, double-blind, placebo-controlled trial of donepezil in patients with Alzheimer's disease. Donepezil Study Group
Rogers SL, Farlow MR, Doody RS, Mohs R, Friedhoff LT
Ref: Neurology, 50:136, 1998 : PubMed
Abstract


ESTHER: Rogers_1998_Neurology_50_136
PubMedSearch: Rogers 1998 Neurology 50 136
PubMedID: 9443470
Inhibitor(s) related to this paper: Aricept~Donepezil~E2020

Abstract

The efficacy and safety of donepezil as a treatment for patients with mild to moderate Alzheimer's disease (AD) was investigated in a multicenter, double-blind study. Patients were randomly assigned to treatment with placebo (n = 162), 5 mg/d donepezil (n = 154), or 10 mg/d donepezil (n = 157) for 24 weeks followed by a 6-week, single-blind placebo washout. The primary efficacy measures were the cognitive portion of the Alzheimer's Disease Assessment Scale (ADAS-cog) and the Clinician's Interview Based Assessment of Change-Plus (CIBIC plus), with the Mini-Mental State Examination (MMSE), Clinical Dementia Rating Scale-Sum of the Boxes (CDR-SB), and patient rated Quality of Life (QoL) used as secondary measures. Cognitive function, as measured by the ADAS-cog, was significantly improved in the 5- and 10-mg/d donepezil groups as compared with the placebo group at weeks 12, 18, and 24. Clinician's global ratings on the CIBIC plus also improved in both the 5- and 10-mg/d donepezil groups relative to placebo. At the end of the 6-week placebo washout phase, ADAS-cog scores and CIBIC plus ratings were not significantly different for the three groups. Significant treatment benefits were also observed consistently in both the 5- and 10-mg/d groups on the MMSE and the CDR-SB, but there was no consistent effect on the patient-rated QoL. Cholinergic side effects (primarily diarrhea, nausea, and vomiting) were reported more often in the 10-mg/d group than either the 5-mg/d or placebo groups. Side effects were transient and generally mild in severity. These data indicate that donepezil is a well-tolerated drug that improves cognition and global function in patients with mild to moderate AD.



        

Title: Long-term efficacy and safety of donepezil in the treatment of Alzheimer's disease: an interim analysis of the results of a US multicentre open label extension study
Rogers SL, Friedhoff LT
Ref: European Neuropsychopharmacology, 8:67, 1998 : PubMed
Abstract


ESTHER: Rogers_1998_Eur.Neuropsychopharmacol_8_67
PubMedSearch: Rogers 1998 Eur.Neuropsychopharmacol 8 67
PubMedID: 9452942
Inhibitor(s) related to this paper: Aricept~Donepezil~E2020

Abstract

The long-term efficacy and safety of donepezil (up to 10 mg/day) was evaluated in a multicentre, non-randomised, open-label extension study of 133 patients with mild to moderate Alzheimer's disease (AD) who had completed a previous 14-week double-blind, placebo-controlled trial of donepezil. Assessments were conducted at three-weekly intervals for 12 weeks, then 12-weekly for up to 192 weeks. Efficacy, assessed by the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog) and Clinical Dementia Rating-Sum of the Boxes (CDR-SB), was examined in comparison with published data of untreated AD patients. Safety was monitored by physical examinations, laboratory tests and vital sign measurements. Results of this interim analysis (at 98 weeks) show that donepezil produced improvements in cognition which remained superior to baseline for 38 weeks. CDR-SB likewise showed improvement, with scores maintained near baseline values for 26 weeks. Scores for both instruments then increased as expected in a progressive disease. However, the slope of score progression was less than has been historically reported for untreated patients. While the lack of a concurrent placebo group does not allow conclusions about the ability of donepezil to attenuate disease progression, the data, nonetheless, demonstrate that there is no loss of treatment benefit over 98 weeks. Donepezil was well tolerated, with no evidence of hepatotoxicity.



        

Title: Perspectives in the Management of Alzheimer's Disease: Clinical Profile of Donepezil
Rogers SL
Ref: Dementia & Geriatric Cognitive Disorders, 9:29, 1998 : PubMed
Abstract


ESTHER: Rogers_1998_Dement.Geriatr.Cogn.Disord_9_29
PubMedSearch: Rogers 1998 Dement.Geriatr.Cogn.Disord 9 29
PubMedID: 9853200

Abstract

Donepezil HCI is a piperidine-based reversible acetylcholinesterase (AChE) inhibitor, chemically distinct from other cholinesterase (ChE) inhibitors and rationally designed to treat the symptoms of Alzheimer's disease (AD). It is highly selective for AChE in the central nervous system (CNS), with little or no affinity for butyrylcholinesterase (BCHE). In preclinical studies in animals, donepezil produced increased CNS acetylcholine. The resultant enhancement of cholinergic activity gave rise to improved performance by rats on tests of learning and memory, with no evidence of hepatic or renal toxicity. In subsequent phase I clinical evaluations in healthy volunteers, donepezil demonstrated favorable pharmacokinetic, pharmacodynamic and safety profiles. Its long terminal disposition half-life supported once-daily administration, with no requirement for dose modification in the elderly or in patients with renal or hepatic impairment. A 14-week, phase II dose-finding study in patients with mild to moderate AD (Clinical Dementia Rating [CDR], 1-2; Mini-Mental State Examination [MMSE], 10-26) showed that donepezil at a dose of 5 mg/day produced highly significant improvements in cognition (as measured by the Alzheimer's Disease Assessment Scale, cognitive subscale [ADAS-cog]). Subsequently, two pivotal parallel-group, placebo-controlled phase III trials (of 15 and 30 weeks' duration) showed highly statistically significant improvements in ADAS-cog, MMSE, Clinician's Interview-Based Impression of Change with caregiver input (CIBIC plus) and CDR-SB (Sum of the Boxes) scores, compared with placebo, in mild to moderate AD patients treated with either 5 or 10 mg/day donepezil. Adverse events in the phase II and III trials were mild and transient and resolved with continued donepezil administration. The donepezil clinical trials program has shown that this drug is a clinically effective and well-tolerated once-daily treatment for the symptoms of mild to moderate AD.



        

Title: Pharmacokinetic and pharmacodynamic profile of donepezil HCl following evening administration
Tiseo PJ, Rogers SL, Friedhoff LT
Ref: British Journal of Clinical Pharmacology, 46 Suppl 1:13, 1998 : PubMed
Abstract


ESTHER: Tiseo_1998_Br.J.Clin.Pharmacol_46 Suppl 1_13
PubMedSearch: Tiseo 1998 Br.J.Clin.Pharmacol 46 Suppl 1 13
PubMedID: 9839760

Abstract

AIMS: The primary objective of this study was to characterize the pharmacokinetics and pharmacodynamics of single daily doses of donepezil (5 and 10 mg) each evening for 28 consecutive days. A secondary objective was to measure the plasma protein binding of donepezil at steady state.
METHODS: This was a double-blind, randomized, multiple-dose study in healthy male (n=13) and female (n=3) volunteers. Subjects were randomized to receive, once daily, either oral doses of 5 mg donepezil for 28 days or doses of 5 mg donepezil for 7 days followed by 10 mg donepezil for 21 days. All doses were administered in the evening. Donepezil concentrations and protein binding in plasma were determined by HPLC with UV detection and equilibrium dialysis, respectively. Inhibition of acetylcholinesterase (AChE) activity in red blood cell (rbc) membranes was assessed using a specific radioenzyme assay.
RESULTS: The pharmacokinetics of donepezil were linear, dose proportional and stationary over the course of the study. Mean Cmax, tmax, AUC(0-24), t1/2 and Vlambda(z)/F at steady state were 34.1 ng ml(-1), 3.0 h, 634.8 ng h ml(-1), 72.7 h, and 11.81 kg(-1), respectively, for the 5 mg group and 60.5 ng ml(-1), 3.9 h, 1127.8 ng h ml(-1), 73.5 h and 11.61 kg(-1), respectively, for the 10 mg group. Accumulation of the drug was observed for 14-21 days, until steady state was achieved. A direct consistent relationship was observed between donepezil plasma concentration and percentage rbc-AChE inhibition during each 24 h evaluation period, indicating no hysteresis in donepezil pharmacodynamics. The pharmacodynamic parameters, Emin, Emax and Ess, were 62.2%, 71.8% and 65.3%, respectively, for the 5 mg donepezil dose, and 74.7%, 83.6% and 77.8%, respectively, for the 10 mg donepezil dose. Donepezil was 95.6% bound to plasma protein at steady state. The binding was high capacity and low affinity, and neither concentration nor time dependent. Both dosage regimens were well tolerated; no clinically significant changes in laboratory or vital sign parameters were observed in any subject.
CONCLUSIONS: The measured pharmacokinetic and pharmacodynamic parameters for both 5 and 10 mg day(-1) donepezil administered in the evening are in good agreement with previous results obtained with morning administration, indicating no time of dosing effect.



        

Title: The efficacy and safety of donepezil in patients with Alzheimer's disease: results of a US Multicentre, Randomized, Double-Blind, Placebo- Controlled Trial. The Donepezil Study Group
Rogers SL, Friedhoff LT
Ref: Dementia, 7:293, 1996 : PubMed
Abstract


ESTHER: Rogers_1996_Dementia_7_293
PubMedSearch: Rogers 1996 Dementia 7 293
PubMedID: 8915035
Inhibitor(s) related to this paper: Aricept~Donepezil~E2020

Abstract

This study evaluated the efficacy and safety of donepezil in patients with mild to moderately severe Alzheimer's disease, and examined the relationships between plasma donepezil concentration, red blood cell acetylcholinesterase (AChE) activity and clinical response. The trial was of a multicenter, double-blind, parallel-group design and patients were randomised to once-daily treatment with either donepezil (1, 3 or 5 mg) or placebo. The 12-week double-blind phase was followed by a 2-week single-blind placebo washout. 161 patients (55-85 years of age) entered the study and 141 completed treatment. Patients treated with donepezil showed dose-related improvements in the Alzheimer's Disease Assessment Scale-cognitive subscale score (ADAS-cog) and in MMSF scores. The improvements in ADAS-cog were statistically significantly greater with donepezil 5 mg/day than with placebo. There was a 50% reduction in the percentage of patients showing clinical decline with donepezil at 5 mg/day (11%) relative to placebo (20%). In addition, a statistically significant correlation between plasma concentrations of donepezil and AChE inhibition was demonstrated. A plateau of inhibition (76-84%) was reached at plasma donepezil concentrations > 50 ng/ml. The correlation between plasma drug concentrations and ADAS-cog (p = 0.014), MMSE (p = 0.023) and patient quality of life scores, assessed by the patient (p = 0.037) were also statistically significant, as was the correlation between AChE inhibition and change in ADAS-cog (p = 0.008). The incidence of treatment-emergent adverse events with all three dosages of donepezil (64-68%) was comparable to that observed with placebo (65%). Donepezil had no clinically significant effect on vital signs, haematology or clinical biochemistry tests. Importantly, donepezil was not associated with any hepatotoxicity, as observed with acridine-based cholinesterase inhibitors.