Donepezil (E-2020) is a reversible, noncompetitive, piperidine-type cholinesterase inhibitor. It is selective for acetylcholinesterase rather than butyrylcholinesterase.
Donepezil 5 and 10 mg/day significantly improved cognition and global clinical function compared with placebo in well designed short term trials (14 to 30 weeks) in 161 to 818 patients with mild to moderate Alzheimer’s disease. Beneficial effects on cognition were observed from week 3 of treatment. Donepezil 10 mg/day significantly delayed the deterioration in activities of daily living (ADL) [by 55 weeks] compared with placebo in a retrospective analysis of 1 trial, and in the largest trial significantly improved patients’ abilities to perform complex tasks. However, no significant improvement in function was observed with donepezil 5 mg/day in another trial. In the 2 trials of longest duration donepezil (5 and 10mg) significantly delayed symptomatic progression of the disease. While there was no evidence for a positive effect of donepezil on patients’ quality of life, there are no validated measures of this parameter specific to patients with Alzheimer’s disease. Donepezil (5 and 10mg) significantly reduced caregiver burden.
Long term efficacy data suggest that improvements in cognition, global function or ADL are maintained for about 21 to 81 weeks with donepezil (10 mg/day in most patients).
Donepezil is generally well tolerated with the majority of adverse events being mild and transient. Predictably, most events were cholinergic in nature and generally related to the gastrointestinal and nervous systems. The incidence of these events was significantly higher with donepezil 10mg than with placebo in short term clinical trials; however, this may have been due to the 7-day dose increase schedule used in these studies and can be minimised by increasing the dose after a longer (6-week) period. The incidence of serious adverse events was generally similar between donepezil 5 and 10mg (4 to 10%) and placebo (5 to 9%) in short term trials. 26% of patients receiving donepezil (5 and 10mg) reported serious events over a 98-week period in a long term trial. Importantly, there was no evidence of hepatotoxicity with this drug.
Conclusions. Donepezil (5 and 10mg) is an agent with a simple once-daily dosage schedule which improves cognition and global clinical function in the short (up to 24 weeks) and long term (up to about 1 year) in patients with mild to moderate Alzheimer’s disease. Improvements in ADL were also observed with donepezil 10 mg/day. Adverse events associated with donepezil are mainly cho- linergic. Donepezil has been extensively studied and should be considered as a first-line treatment in patients with mild to moderate Alzheimer’s disease.
Donepezil is defined as a mixed inhibitor of acetylcholinesterase exhibiting primarily noncompetitive, but also some competitive, inhibition of this enzyme.
Donepezil inhibited acetylcholinesterase (from the electric eel and human erythrocyte) more potently than tacrine in in vitro studies.
As with other cholinesterase inhibitors, donepezil less potently inhibited acetylcholinesterase from senile plaques in the cortex of patients with moderate to severe Alzheimer’s disease than that from other fractions of diseased brain or from the cortex of individuals with no neurological disease in an in vitro study.
Donepezil selectively inhibits acetylcholinesterase rather than butyrylcholin-esterase and was more selective for this enzyme than tacrine and physostigmine in in vitro and ex vivo (rat) studies. The ratio of the concentrations of donepezil needed to produce a 50% inhibition (IC50) of human butyrylcholinesterase to the IC50 of acetylcholinesterase was 405: 1.
Acetylcholinesterase in skeletal muscle (rodent) was inhibited to a greater extent by donepezil than that from the brain (rodent) or erythrocytes (human). A similar effect was observed with tacrine, rivastigmine and physostigmine, although donepezil inhibited all 3 isoenzymes more potently than these agents. However, in another study donepezil more potently inhibited cholinesterase from rodent brain than that from the plasma, heart or pectoral muscle. In contrast, tacrine less potently inhibited brain cholinesterase than that in other tissues.
The inhibitory effects of donepezil on erythrocyte acetylcholinesterase appears to correspond closely to that in the rodent cortex. Donepezil dose-relatedly inhibits erythrocyte acetylcholinesterase, as shown in studies in patients with Alzheimer’s disease receiving dosages of 1 to 10 mg/day for 12 to 98 weeks. Mean percentage inhibition was 64% with donepezil 5mg and 75 to 77% with donepezil 10mg at 6 or 12 weeks.
Donepezil significantly increased extracellular acetylcholine levels in rat hippocampus and cortex and was more potent than tacrine in producing this effect. Extracellular noradrenaline (norepinephrine) and dopamine, but not serotonin (5-hydroxytryptamine; 5-HT), levels in the cortex were increased by donepezil in rats.
Donepezil produced centrally-mediated cholinergic effects in rodent models. No peripherally-mediated effects were observed in 1 study but were apparent in another study. However, some peripheral effects were more prominent, and both types of effects persisted for longer, with tacrine.
Induced deficits in working and reference memory and attention are significantly reversed by donepezil, as shown in various animal models of cognitive impairment. Similarly, donepezil attenuated naturally occurring memory deficits in young rats. In general, donepezil is more potent than tacrine at enhancing cognition and attention according to animal studies.
The maximum plasma concentration (Cmax), area under the plasma concentration-time curve (AUC) and the mean donepezil concentration at steady state are linearly proportional to dosage but clearance is independent of dose, as seen in single or multiple dose studies in volunteers.
After single dose oral donepezil (5 to 10mg) the Cmax (7.2 to 25.6 μg/L) is achieved in 2.4 to 4.4 hours [time to Cmax (tmax)], as seen in volunteers. The AUC ranges from about 500 to 1000 μg/L and the volume of distribution (Vd) from about 755 to 837L (or 14 L/kg with donepezil 5mg). The absorption of donepezil is not affected by the presence of food. Donepezil is highly protein bound (about 93 to 96%).
After repeated administration (5 or 10 mg/day for 21 or 28 days), steady state is achieved within 14 to 22 days. Generally, tmax and Vd values are similar to those observed with single dose donepezil, but Cmax appears to be higher.
Donepezil is largely metabolised by the cytochrome P450 isoenzymes 3A4 and 2D6, and undergoes extensive first-pass metabolism. The main metabolites are a hydrolysis product, 2 glucuronide conjugates and an oxidation product. Only 1 of these metabolites is active and has similar activity to that of the parent drug. Elimination of donepezil and its metabolites is primarily via the renal route.
After single doses of donepezil 5 to 10mg, the elimination half-life (t½), renal clearance (CLr) and total body clearance (CL) were independent of dose, as seen in volunteers. CL at steady state appears to be similar to values achieved after single doses but t½ appears to be longer than that observed with the corresponding single dose.
In elderly patients receiving single doses of donepezil 2mg, tmax, mean residence time and t½ were significantly longer and Vd was significantly greater than values in young volunteers. In general, impaired renal or hepatic function do not affect the pharmacokinetic parameters of donepezil, as observed in single dose studies. Cmax was significantly higher (37.5%) in patients with impaired hepatic function compared with healthy volunteers, although this was not considered to be clinically significant.
Donepezil does not have clinically significant effects on the pharmacokinetic parameters of digoxin, theophylline, warfarin, ketoconazole or cimetidine. Further, neither ketoconazole nor cimetidine have clinically significant effects on donepezil pharmacokinetics.
Donepezil 5 and 10 mg/day significantly improved cognition and global clinical function in trials of 14 to 30 weeks duration (including 2- to 6-week placebo-washout periods). In these trials in 161 to 818 patients with mild to moderate Alzheimer’s disease, the Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-cog), Mini-Mental Status Examination (MMSE) and Clinician’s Interview-Based Impression of Change (CIBIC plus) scores significantly improved compared with placebo, and significantly fewer donepezil recipients had treatment failure according to Clinical Global Impression of Change scores. Furthermore, clinically meaningful improvements were observed in more patients receiving donepezil 5 and 10mg than placebo according to various parameters; a change of ≥4 points from baseline in ADAS-cog (about 38% with donepezil 5mg and 54 or 60% with donepezil 10mg vs 27 or 30% with placebo), no decline in ADAS-cog scores (about 80% with donepezil 5 and 10mg vs 58% with placebo) and a score of ≤3 in CIBIC plus (21 to 32% with donepezil 5mg and 25 to 38% with donepezil 10mg vs 11 to 18% with placebo). Significant changes in cognition were observed from 3 weeks of the start of treatment.
Donepezil 10 mg/day significantly improved patients’ abilities to perform complex tasks compared with placebo in the largest trial, and in a retrospective Kaplan-Meier analysis of another trial, donepezil 10 mg/day delayed the loss of ADL by 55 weeks compared with placebo. Donepezil 5 mg/day did not significantly improve function according to the activities of daily living (ADL) scale in 1 trial. In the 2 trials of longest duration Clinical Dementia Rating Scale-Sums of Boxes (CDR-SB) scores significantly improved with donepezil (5 and 10 mg/day) compared with placebo, thus suggesting that donepezil slows symptomatic progression of the disease.
Although, donepezil 5 and 10 mg/day generally does not appear to improve patients’ quality of life, no quality-of-life assessment has been validated in this group of patients. Donepezil 5 and 10mg significantly reduced caregiver burden according to 2 preliminary study reports.
When donepezil treatment was stopped during a 2- to 6-week placebo-washout period, all efficacy parameters tended towards or were worse than (generally not statistically significant vs placebo) baseline values, thus indicating a deterioration in symptoms on drug withdrawal. However, a rebound effect on treatment withdrawal is not expected according to the manufacturers’ prescribing information.
There was a significant correlation between plasma donepezil concentrations, the level of erythrocyte acetylcholinesterase inhibition and changes in cognition or global function.
In 2 nonblind, noncomparative long term extensions of short term trials in patients with mild to moderate Alzheimer’s disease, improvements in cognition and global clinical function were maintained until weeks 38 to 51 and 26 to 39, respectively, with donepezil (generally 10 mg/day). After this time, ADAS-cog and CDR-SB scores deteriorated, representing disease progression, but donepezil delayed the deterioration compared with that expected in untreated patients. In a preliminary report of another trial, cognition (assessed by ADAS-cog) was maintained for up to about 81 weeks with donepezil 10 mg/day in patients showing a response to treatment. Similarly, compared with placebo, global clinical function and cognition significantly improved from weeks 24 to 52 and ADL improved at week 52 with donepezil 10 mg/day in a preliminary report of the first long term double-blind, randomised long term (52 weeks) trial. In another 1-year double-blind, randomised trial donepezil 10 mg/day significantly delayed the median time to clinically significant loss of function by about 21 weeks (5 months).
Donepezil doses recommended in Japan are lower than those employed elsewhere. Two short term trials (8 or 12 weeks) and 1 long term study (24 to 48 weeks) conducted in Japan in 39 to 187 patients with mild to moderate Alzheimer’s disease receiving these lower doses (2 to 5 mg/day) generally did not support the findings of these previously mentioned studies. However, donepezil 5 mg/day significantly improved ADAS-Jcog (Japanese version of ADAS-cog) and final global improvement rating (FGIR) scores in a short term trial when only patients with mild to moderate Alzheimer’s disease whose baseline ADAS-Jcog scores were ≥15 were assessed.
Donepezil is generally well tolerated. Most adverse events are mild, transient and cholinergic in nature.
In short term trials (12 to 24 weeks’ treatment) in patients with mild to moderate Alzheimer’s disease, the overall incidence of adverse events appeared to be similar between donepezil 5 mg/day (67 or 79%) and placebo (65 to 76%) but higher with donepezil 10 mg/day (78 or 86%). Compared with withdrawal rates observed with placebo (1 to 10%), the incidence of treatment discontinuation appeared to be similar with donepezil 5mg (4 to 9%) but higher with the 10mg dosage (9 to 18%). Individual adverse events occurring more frequently with donepezil (5 and 10mg) than with placebo were generally related to the gastrointestinal system, but also included insomnia, fatigue and muscle cramps. In the largest trial gastrointestinal and nervous system adverse events were significantly more common with donepezil (5 and 10mg) than with placebo. The high incidence of these events with donepezil 10mg was probably due to the rapid increase (after 1 week) to this dose level, and can be reduced by increasing the dose over a 6-week period.
After long term treatment (98 weeks) the overall cumulative incidence of adverse events with donepezil (10 mg/day in most patients) was 83% and adverse events resulted in treatment discontinuation in 4% of patients in a sole trial. The most common events in this trial were agitation, dizziness, pain, urinary tract infection, diarrhoea, common cold, upper respiratory tract infection, headache, nausea, confusion, insomnia and accidents (incidence >5%).
The incidence of serious adverse events was greater with donepezil 10mg (10%) than with the 5mg dosage (5%) or placebo (6%) in 1 short term trial, but a similar incidence was observed between donepezil (5 and 10mg) and placebo in other trials (4 vs 5% and 9 vs 9%). After long term use serious adverse events occurred in 26% of donepezil recipients over a 98-week period, but most were considered not to be related to treatment. Serious events led to treatment discontinuation by 7% of patients in the long term trial.
Heart rate decreased with donepezil (5 and 10mg) but this was not considered clinically significant and the incidence of bradycardia with donepezil did not differ significantly from that observed with placebo.
No clinically significant changes to vital signs or haematological or biochemical parameters are observed with donepezil and, importantly, hepatotoxicity has not occurred.
Dosage and Administration
Donepezil is indicated in patients with mild to moderate Alzheimer’s disease. In countries other than Japan it is recommended that treatment should be initiated with a 5mg dose administered orally at night, and should be given for 4 to 6 weeks before increasing the daily dose to 10mg.
In Japan, treatment is initiated with a 3mg daily dosage which is increased to 5 mg/day after 1 to 2 weeks.
Donepezil does not interfere with the metabolism of theophylline, warfarin, cimetidine or digoxin, and neither cimetidine nor digoxin affect the metabolism of donepezil. Donepezil does not appear to interact with selective serotonin reuptake inhibitors, antipsychotics or anti-Parkinsonian treatment, as seen in long term studies. No significant interaction is observed between donepezil and ketoconazole according to a short term trial in healthy volunteers. However, there is potential for pharmacodynamic interaction with anticholinergic drugs, succinylcholine and other neuromuscular blocking agents, and cholinergic agonists.
Cholinesterase inhibitors may augment the actions of succinylcholine and other muscle relaxants, have vagotonic effects on heart rate and may have the potential to cause generalised seizures. Patients with a history of asthma or obstructive pulmonary disease should be prescribed these drugs with care, and those at risk of developing ulcers should be monitored while receiving these agents.
KeywordsCholinesterase Inhibitor Rivastigmine Tacrine Physostigmine Short Term Trial
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