Friedhoff LT

References (16)

Title : The effects of donepezil in Alzheimer's disease - results from a multinational trial - Burns_1999_Dement.Geriatr.Cogn.Disord_10_237
Author(s) : Burns A , Rossor M , Hecker J , Gauthier S , Petit H , Moller HJ , Rogers SL , Friedhoff LT
Ref : Dementia & Geriatric Cognitive Disorders , 10 :237 , 1999
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.
ESTHER : Burns_1999_Dement.Geriatr.Cogn.Disord_10_237
PubMedSearch : Burns_1999_Dement.Geriatr.Cogn.Disord_10_237
PubMedID: 10325453

Title : Pharmacokinetic and pharmacodynamic profile of donepezil HCl following multiple oral doses - Rogers_1998_Br.J.Clin.Pharmacol_46 Suppl 1_7
Author(s) : Rogers SL , Cooper NM , Sukovaty R , Pederson JE , Lee JN , Friedhoff LT
Ref : British Journal of Clinical Pharmacology , 46 Suppl 1 :7 , 1998
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.
ESTHER : Rogers_1998_Br.J.Clin.Pharmacol_46 Suppl 1_7
PubMedSearch : Rogers_1998_Br.J.Clin.Pharmacol_46 Suppl 1_7
PubMedID: 9839759

Title : Pharmacokinetic and pharmacodynamic profile of donepezil HCl following single oral doses - Rogers_1998_Br.J.Clin.Pharmacol_46 Suppl 1_1
Author(s) : Rogers SL , Friedhoff LT
Ref : British Journal of Clinical Pharmacology , 46 Suppl 1 :1 , 1998
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.
ESTHER : Rogers_1998_Br.J.Clin.Pharmacol_46 Suppl 1_1
PubMedSearch : Rogers_1998_Br.J.Clin.Pharmacol_46 Suppl 1_1
PubMedID: 9839758

Title : The effect of multiple doses of donepezil HCl on the pharmacokinetic and pharmacodynamic profile of warfarin - Tiseo_1998_Br.J.Clin.Pharmacol_46 Suppl 1_45
Author(s) : Tiseo PJ , Foley K , Friedhoff LT
Ref : British Journal of Clinical Pharmacology , 46 Suppl 1 :45 , 1998
Abstract : AIM: The aim of the study was to examine the pharmacokinetic and pharmacodynamic profiles of single doses of warfarin (25 mg) following administration alone, and in combination with multiple doses of donepezil HCl (10 mg day(-1)) in healthy volunteers.
METHODS: This was an open-label, two-period crossover study in 12 healthy male volunteers, aged 18-55 years, who were randomized to one of the following treatment groups: (A) donepezil administered for 19 consecutive days with a single dose of warfarin administered on day 14. On day 20, there was a 21-day washout period after which a single dose of warfarin was again administered, and (B) an initial 13-day period with no medication, then a single dose of warfarin administered alone on day 14, followed by a 14-day washout period. Donepezil was then administered for 19 days (to day 47), with an additional single dose of warfarin administered on day 41. Serial blood samples were collected over 144 h following both warfarin administrations in each treatment group. Pharmacokinetic parameters were assessed for both (R)- and (S)-warfarin concentrations in plasma, and pharmacodynamic analyses utilizing prothrombin time were undertaken. Warfarin concentrations in plasma were determined by HPLC with fluorescence detection. The pharmacokinetic parameters Cmax, AUC(0-infinity), CL(T)/F, Vlambdaz/F and t1/2 of both (R)- and (S)-warfarin, maximum prothrombin time (Rmax) and the area under the prothrombin-time curve (AUC(PT)), were compared in the presence and absence of donepezil by analysis of variance (ANOVA).
RESULTS: No statistically significant differences in (R)- or (S)-warfarin pharmacokinetics were observed when warfarin administered alone was compared to warfarin administered concurrently with donepezil. Warfarin pharmacodynamic parameters, Rmax and AUC(PT), were also unchanged by concomitant administration ofdonepezil. No clinically significant changes in vital signs, ECG parameters or clinical laboratory tests were observed.
CONCLUSIONS: Concurrent administration of donepezil HCl does not alter the pharmacokinetic or pharmacodynamic profile of single doses of warfarin in healthy volunteers. These findings suggest that donepezil may be safely co-administered with warfarin without the need for dose modification.
ESTHER : Tiseo_1998_Br.J.Clin.Pharmacol_46 Suppl 1_45
PubMedSearch : Tiseo_1998_Br.J.Clin.Pharmacol_46 Suppl 1_45
PubMedID: 9839766

Title : An evaluation of the pharmacokinetics of donepezil HCl in patients with moderately to severely impaired renal function - Tiseo_1998_Br.J.Clin.Pharmacol_46 Suppl 1_56
Author(s) : Tiseo PJ , Foley K , Friedhoff LT
Ref : British Journal of Clinical Pharmacology , 46 Suppl 1 :56 , 1998
Abstract : AIM: The aim of this study was to evaluate the pharmacokinetics of donepezil HCl (5 mg) in patients with moderately to severely impaired renal function (creatinine clearance: <30 ml min(-1) 1.73 m(-2)), following the administration of single oral doses.
METHODS: This was an open-label, non-randomized study in patients with compromised renal function (n=11), and in age- and gender-matched healthy controls (n =11). Each subject received a single oral dose of 5 mg donepezil. Blood samples for pharmacokinetic measurements were taken at specified intervals for 17 days post-dose. Concentrations of donepezil in plasma were measured by HPLC with UV detection.
RESULTS: There were no statistical differences between the two groups for any of the pharmacokinetic parameters evaluated (ANOVA). Cmax (mean +/- SD) was 7.7+/-1.2 ng ml(-1) in healthy subjects and 8.3+/-3.2 ng ml(-1) in renally impaired patients. AUC(0-infinity) in healthy subjects and in renally impaired patients was 539+/-115 ng h ml(-1) and 640+/-150 ng h ml(-1), respectively. The mean half-life of donepezil was 86.7+/-23.3 h in healthy subjects and 91.3+/-40.9 h in the renally impaired patients. The drug was well tolerated by all study participants. There were no clinically significant changes in vital signs, clinical chemistry or ECG parameters.
CONCLUSIONS: These findings suggest that the pharmacokinetics of donepezil do not change in patients with moderately to severely impaired renal function.
ESTHER : Tiseo_1998_Br.J.Clin.Pharmacol_46 Suppl 1_56
PubMedSearch : Tiseo_1998_Br.J.Clin.Pharmacol_46 Suppl 1_56
PubMedID: 9839768

Title : Concurrent administration of donepezil HCl and cimetidine: assessment of pharmacokinetic changes following single and multiple doses - Tiseo_1998_Br.J.Clin.Pharmacol_46 Suppl 1_25
Author(s) : Tiseo PJ , Perdomo CA , Friedhoff LT
Ref : British Journal of Clinical Pharmacology , 46 Suppl 1 :25 , 1998
Abstract : AIM: The aim of this study was to examine the pharmacokinetics of donepezil HCl and cimetidine separately, and in combination, following administration of multiple oral doses.
METHODS: This was an open-label, randomized, three-period crossover study in healthy male volunteers (n=19). During each treatment period, subjects received single daily doses of either donepezil HCl (5 mg), cimetidine (800 mg), or a combination of both drugs for 7 consecutive days. Pharmacokinetic comparisons were made between groups for the day 1 and day 7 profiles. Each treatment period was followed by a 3-week, drug-free washout period.
RESULTS: On both day 1 and day 7, a statistically significant difference was observed between the donepezil and the donepezil + cimetidine groups in terms of the Cmax and AUC(0-24) values for donepezil. The combination group had an 11-13% greater Cmax and a 10% greater AUC(0-24) than the donepezil-only group. No significant difference was observed between the tmax of the two treatment groups on day 1, and no significant differences in tmax, t1/2 or the rate of drug accumulation (RA) were observed between the groups on day 7. Cimetidine pharmacokinetics were essentially unchanged by co-administration of the two drugs. The donepezil + cimetidine treatment group had a 20% greater maximum cimetidine concentration (Cmax) than the cimetidine-only group (P= 0.001) on day 1, but not on day 7, and no difference was observed in any of the other pharmacokinetic parameters examined.
CONCLUSIONS: Co-administration of donepezil HCl (5 mg) and cimetidine (800 mg) did not produce clinically significant changes in the pharmacokinetic profiles of either drug.
ESTHER : Tiseo_1998_Br.J.Clin.Pharmacol_46 Suppl 1_25
PubMedSearch : Tiseo_1998_Br.J.Clin.Pharmacol_46 Suppl 1_25
PubMedID: 9839762

Title : Concurrent administration of donepezil HCl and digoxin: assessment of pharmacokinetic changes - Tiseo_1998_Br.J.Clin.Pharmacol_46 Suppl 1_40
Author(s) : Tiseo PJ , Perdomo CA , Friedhoff LT
Ref : British Journal of Clinical Pharmacology , 46 Suppl 1 :40 , 1998
Abstract : AIM: The aim of this study was to examine the pharmacokinetics of donepezil HCl and digoxin separately, and in combination, following administration of single oral doses. Changes in cardiac conduction parameters following drug administration were also assessed.
METHODS: This was an open-label, randomized, three-period crossover study in healthy male volunteers (n=12). During each treatment period, subjects received a single dose of either donepezil HCl (5 mg), digoxin (0.25 mg), or a combination of both drugs. Each treatment period was followed by a 2-week, drug-free washout period.
RESULTS: All 12 volunteers completed the study without incident. No statistically significant differences in donepezil pharmacokinetics (Cmax, tmax, AUC(0-120), AUC(0-infinity) or t1/2) were observed when donepezil administered alone was compared with donepezil administered in combination with digoxin. Similarly, no statistically significant differences in digoxin pharmacokinetics were observed when digoxin was administered alone or in combination with donepezil. No clinically relevant changes in cardiac conduction (lead II ECG) were observed in any subject during any treatment period.
CONCLUSIONS: Co-administration of single doses of donepezil HCl (5 mg) and digoxin (0.25 mg) produced no changes in the pharmacokinetic profile of either drug. In addition, co-administration produced no changes in cardiac conduction parameters during the 24 h of telemetry monitoring following drug administration.
ESTHER : Tiseo_1998_Br.J.Clin.Pharmacol_46 Suppl 1_40
PubMedSearch : Tiseo_1998_Br.J.Clin.Pharmacol_46 Suppl 1_40
PubMedID: 9839765

Title : Metabolism and elimination of 14C-donepezil in healthy volunteers: a single-dose study - Tiseo_1998_Br.J.Clin.Pharmacol_46 Suppl 1_19
Author(s) : Tiseo PJ , Perdomo CA , Friedhoff LT
Ref : British Journal of Clinical Pharmacology , 46 Suppl 1 :19 , 1998
Abstract : AIM: The aim of this study was to investigate the metabolism and elimination of donepezil HCl in humans, following the administration of a single 5 mg (liquid) oral dose containing a mixture of unlabelled and 14C-labelled donepezil.
METHODS: This was an open-label, non-randomized study in healthy male volunteers (n = 8). Characterization of donepezil metabolism and elimination was performed by analysing blood, urine and faecal samples collected over a 10-day period following drug administration. Each collected sample was assayed for total radioactivity, and aliquots from specified time-points and/or pooled samples were assayed for the presence of donepezil metabolites by thin-layer chromatography (TLC). Donepezil concentrations in plasma were determined by HPLC.
RESULTS: Recovery of radioactivity in subject samples averaged 72% of the administered dose. Recovery of the administered dose in urine (57%) was significantly greater than that recovered in faeces (15%). Unchanged donepezil accounted for the largest component of the recovered dose in each matrix. Three metabolic pathways were identified: (i) O-dealkylation and hydroxylation to metabolites M1 and M2, with subsequent glucuronidation to metabolites M11 and M12; (ii) hydrolysis to metabolite M4; and (iii) N-oxidation to metabolite M6. In plasma, the parent compound accounted for about 25% of the dose recovered during each sampling period, as well as of the cumulative dose recovered. The recovered residue showed higher levels of the hydroxylated metabolites M1 and M2 than of their glucuronide conjugates M11 and M12, respectively. In urine, the parent compound accounted for 17%, on average, of the dose recovered from each pooled sample, as well as of the total recovered dose. The major metabolite was the hydrolysis product M4, followed by the glucuronidated conjugates M11 and M12. In faeces, the parent compound also predominated, although it accounted for only 1%, of the recovered dose. A large percentage of the radioactivity in faeces consisted of unidentified very polar metabolites, which were retained at the TLC origin. Of the extracted metabolites, the hydroxylation products M1 and M2 were the most abundant, followed by the hydrolysis product M4 and the N-oxidation product M6.
CONCLUSIONS: Donepezil is hepatically metabolized and the predominant route for the elimination of both parent drug and its metabolites is renal, as 79% of the recovered dose was found in the urine with the remaining 21% found in the faeces. Moreover, the parent compound, donepezil, is the predominant elimination product in urine. The major metabolites of donepezil include M1 and M2 (via O-dealkylation and hydroxylation), M11 and M12 (via glucuronidation of M1 and M2, respectively), M4 (via hydrolysis) and M6 (via N-oxidation).
ESTHER : Tiseo_1998_Br.J.Clin.Pharmacol_46 Suppl 1_19
PubMedSearch : Tiseo_1998_Br.J.Clin.Pharmacol_46 Suppl 1_19
PubMedID: 9839761

Title : Pharmacokinetic and pharmacodynamic profile of donepezil HCl following evening administration - Tiseo_1998_Br.J.Clin.Pharmacol_46 Suppl 1_13
Author(s) : Tiseo PJ , Rogers SL , Friedhoff LT
Ref : British Journal of Clinical Pharmacology , 46 Suppl 1 :13 , 1998
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.
ESTHER : Tiseo_1998_Br.J.Clin.Pharmacol_46 Suppl 1_13
PubMedSearch : Tiseo_1998_Br.J.Clin.Pharmacol_46 Suppl 1_13
PubMedID: 9839760

Title : An evaluation of the pharmacokinetics of donepezil HCl in patients with impaired hepatic function - Tiseo_1998_Br.J.Clin.Pharmacol_46 Suppl 1_51
Author(s) : Tiseo PJ , Vargas R , Perdomo CA , Friedhoff LT
Ref : British Journal of Clinical Pharmacology , 46 Suppl 1 :51 , 1998
Abstract : AIM: The aim of this study was to evaluate the pharmacokinetic profile of donepezil HCl (5 mg) in patients with impaired hepatic function, following the administration of single oral doses.
METHODS: This was an open-label, non-randomized study comparing the pharmacokinetic profile of donepezil in male volunteers with chronic compensated cirrhosis of the liver (n = 10) to that in healthy age- and sex-matched controls (n = 10). Each subject received a single 5 mg oral dose of donepezil. Blood samples for pharmacokinetic analyses were taken at specified intervals up to 120-h post-dose. Concentrations of donepezil in plasma were determined by HPLC with UV detection.
RESULTS: No statistically significant differences in donepezil pharmacokinetics were observed between hepatically impaired patients and normal subjects, with the exception of Cmax. The hepatically impaired patients showed a statistically significant, but not clinically significant, higher mean Cmax value of 6.6 ng ml(-1) compared with the control group, which had a mean Cmax value of 4.8 ng ml(-1) (P=(0.022). This represented an increase of 37.5%. The observed changes in AUC values were smaller and not statistically different. The AUC(0-120) and AUC(0-infinity) were 7% and 21% larger in the hepatically impaired patients than in the normal subjects, respectively, although clearance and volume of distribution were almost identical in the two groups. The t1/2 increased by 20%, but this change was also not statistically significant. Donepezil was equally well tolerated by all subjects.
CONCLUSIONS: This study demonstrates that compromised hepatic function does not produce clinically significant changes in the pharmacokinetics of donepezil following single-dose administration. These results suggest that the administration of donepezil to patients with hepatic disease in clinical practice should not require any dosing modifications.
ESTHER : Tiseo_1998_Br.J.Clin.Pharmacol_46 Suppl 1_51
PubMedSearch : Tiseo_1998_Br.J.Clin.Pharmacol_46 Suppl 1_51
PubMedID: 9839767

Title : Donepezil improves cognition and global function in Alzheimer disease: a 15-week, double-blind, placebo-controlled study. Donepezil Study Group - Rogers_1998_Arch.Intern.Med_158_1021
Author(s) : Rogers SL , Doody RS , Mohs RC , Friedhoff LT
Ref : Archives of Internal Medicine , 158 :1021 , 1998
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.
ESTHER : Rogers_1998_Arch.Intern.Med_158_1021
PubMedSearch : Rogers_1998_Arch.Intern.Med_158_1021
PubMedID: 9588436

Title : A 24-week, double-blind, placebo-controlled trial of donepezil in patients with Alzheimer's disease. Donepezil Study Group - Rogers_1998_Neurology_50_136
Author(s) : Rogers SL , Farlow MR , Doody RS , Mohs R , Friedhoff LT
Ref : Neurology , 50 :136 , 1998
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.
ESTHER : Rogers_1998_Neurology_50_136
PubMedSearch : Rogers_1998_Neurology_50_136
PubMedID: 9443470

Title : Concurrent administration of donepezil HCl and ketoconazole: assessment of pharmacokinetic changes following single and multiple doses - Tiseo_1998_Br.J.Clin.Pharmacol_46 Suppl 1_30
Author(s) : Tiseo PJ , Perdomo CA , Friedhoff LT
Ref : British Journal of Clinical Pharmacology , 46 Suppl 1 :30 , 1998
Abstract : AIM: The aim of this study was to examine the pharmacokinetics of donepezil HCl and ketoconazole separately, and in combination, following administration of single and multiple oral doses.
METHODS: This was an open-label, randomized, three-period crossover study in healthy volunteers (n=21). During each treatment period, subjects received single daily doses of either donepezil HCl (5 mg), ketoconazole (200 mg), or a combination of both drugs for 7 consecutive days. Pharmacokinetic comparisons were made between treatment groups for the day 1 and day 7 profiles. Each treatment period was followed by a 3-week, drug-free washout period.
RESULTS: On both day 1 and day 7, a statistically significant difference was observed between the donepezil and the donepezil + ketoconazole treatment groups in terms of Cmax and AUC(0-24) of donepezil. The concurrent administration of both drugs resulted in a 12% greater Cmax (9.5 ng ml(-1) versus 8.4 ng ml(-1); P=0.01) and a 12% greater AUC(0-24) (135.2 ng h ml(-1) versus 118.7 ng h ml(-1); P=0.001) than donepezil alone on day 1, and a 26.8% greater Cmax (37.7 ng ml(-1) versus 27.6 ng ml(-1); P < 0.0001) and a 26.4% greater AUC(0-24) (680.9 ng h ml(-1) versus 501.0 ng h ml(-1); P<0.0001) than donepezil alone on day 7. In contrast, ketoconazole plasma concentrations were unaffected by the concurrent administration of donepezil, and there were no statistically significant differences in ketoconazole pharmacokinetics when ketoconazole administered alone was compared with ketoconazole administered with donepezil.
CONCLUSIONS: The concurrent administration of ketoconazole and donepezil produces no change in ketoconazole plasma concentrations, but a statistically significant change in donepezil plasma concentrations. These observed changes, which are smaller than those produced by ketoconazole for other agents sharing the CYP-3A4 pathway, are most likely the result of donepezil also being metabolized by CYP-2D6, as well as its slow rate of clearance from plasma.
ESTHER : Tiseo_1998_Br.J.Clin.Pharmacol_46 Suppl 1_30
PubMedSearch : Tiseo_1998_Br.J.Clin.Pharmacol_46 Suppl 1_30
PubMedID: 9839763

Title : Concurrent administration of donepezil HCl and theophylline: assessment of pharmacokinetic changes following multiple-dose administration in healthy volunteers - Tiseo_1998_Br.J.Clin.Pharmacol_46 Suppl 1_35
Author(s) : Tiseo PJ , Foley K , Friedhoff LT
Ref : British Journal of Clinical Pharmacology , 46 Suppl 1 :35 , 1998
Abstract : AIM: The aim of the study was to evaluate the pharmacokinetics of theophylline administered alone, and in combination with donepezil HCl, following multiple-dose administration of both drugs in healthy volunteers.
METHODS: This was an open-label, randomized, two-period crossover study in healthy male volunteers (n=12). During each treatment period, subjects received either titrated-dose theophylline alone, or in combination with donepezil (5 mg, once daily) for 10 consecutive days. On day 10 of each treatment period, serial blood samples for the determination of theophylline concentrations in plasma were measured up to 24 h. Treatment periods were separated by a 3-week, drug-free washout. Plasma concentrations of theophylline were determined by HPLC with UV detection.
RESULTS: No statistically significant differences in theophylline pharmacokinetics (Cmax, AUC or tmax) were observed between theophylline administered alone and in combination with donepezil. No clinically significant changes in vital signs, ECG parameters or clinical laboratory tests were observed in any subject during any treatment period.
CONCLUSIONS: Concurrent administration of donepezil HCl does not alter the pharmacokinetic profile of theophylline following multiple-dose administration of both drugs in healthy volunteers. These findings suggest that donepezil may be safely co-administered with theophylline without a need for dose modification or additional monitoring procedures.
ESTHER : Tiseo_1998_Br.J.Clin.Pharmacol_46 Suppl 1_35
PubMedSearch : Tiseo_1998_Br.J.Clin.Pharmacol_46 Suppl 1_35
PubMedID: 9839764

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_1998_Eur.Neuropsychopharmacol_8_67
Author(s) : Rogers SL , Friedhoff LT
Ref : European Neuropsychopharmacology , 8 :67 , 1998
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.
ESTHER : Rogers_1998_Eur.Neuropsychopharmacol_8_67
PubMedSearch : Rogers_1998_Eur.Neuropsychopharmacol_8_67
PubMedID: 9452942

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_1996_Dementia_7_293
Author(s) : Rogers SL , Friedhoff LT
Ref : Dementia , 7 :293 , 1996
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.
ESTHER : Rogers_1996_Dementia_7_293
PubMedSearch : Rogers_1996_Dementia_7_293
PubMedID: 8915035