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

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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.

Introduction

Alzheimer's disease (AD) primarily affects the elderly. Epidemiological research suggests a prevalence of some 5–10% in those aged 65 years and older, increasing to approximately 50% in those older than 85 years of age (Kaplan and Sadock, 1995). Since there are no recognised biological markers of the disease, diagnosis is usually based on clinical diagnostic criteria such as the DSM-IV (Diagnostic and Statistical Manual of Mental Disorder IV [American Psychiatric Association, 1994]) and NINCDS-ADRDA (National Institute of Neurological and Communicative Disorders and Alzheimer's Disease and Related Disorders Association [McKhann et al., 1984]).

The aetiology of AD remains uncertain, although the presence of amyloid plaques and neurofibrillary tangles are a characteristic feature at autopsy. Some of the symptoms of AD are thought to be due to a decrease in cholinergic innervation of the cerebral cortex and basal forebrain, a theory consistent with the cognitive deficits seen in AD patients (Becker, 1991). This theory has led to the development of drugs designed to increase the activity of cholinergic systems in the CNS. Cholinesterase (ChE) inhibitors represent one such class of agents. They increase the concentration of acetylcholine (ACh) available for synaptic transmission through inhibition of enzymes which hydrolyse it, i.e. butyrylcholinesterase (BuChE) and acetylcholinesterase (AChE) (Rogers et al., 1991). AChE is the prime target of therapeutic intervention because it acts centrally on synaptic function.

The two earliest developed classes of ChE inhibitors are the acridines (e.g. tacrine) and the carbamates (e.g. physostigmine, ENA 713). However, neither class is considered an ideal treatment for Alzheimer's disease because of their short half-lives and unfavourable side-effect profile. Also most of these agents lack of selectivity for AChE causing significant BuChE inhibition and resultant unwanted peripheral cholinergic side-effects (Summers et al., 1986, Stern et al., 1988, Davis et al., 1992). Tacrine, a drug marketed in the US and several European markets, in particular is associated with dose-limiting hepatic toxicity (Summers et al., 1986). Given these limitations, there remains a need for a long-acting, selective, well-tolerated AChE inhibitor.

Donepezil (E2020; (±)-2,3-dihydro-5,6-dimethoxy-2[[1-(phenylmethyl)-4- piperidinyl]methyl]-1H-inden-1-one hydrochloride), developed for the treatment of Alzheimer's disease, is a novel piperidine-based derivative and chemically distinct from other cholinesterase inhibitors (Cardozo et al., 1992a, Cardozo et al., 1992b, Sugimoto et al., 1992). Preclinical studies have shown it to be highly selective for AChE in the CNS and to have a longer duration of inhibitory action than either physostigmine or tacrine (Yamanishi et al., 1990, Rogers et al., 1991). Its lack of peripheral activity is demonstrated by the fact that, whilst it significantly inhibits brain cholinesterase, it has no effect on either cardiac muscle or smooth muscle in the intestine and has only a limited effect on ChE in pectoral (striated) muscle (Rogers et al., 1991).

The lack of toxicity associated with the administration of donepezil has been demonstrated in preclinical toxicology studies, which revealed no long-term unexpected toxicity or evidence of hepatotoxicity (Rogers et al., 1991). Phase I, II and III clinical studies have also shown donepezil at doses of 5 mg/day and 10 mg/day to be well tolerated and to lack the dose-limiting hepatotoxicity produced by acridine-based agents like tacrine (Mihara et al., 1993, Rogers and Friedhoff, 1994, Rogers et al., 1996a, Rogers et al., 1996b).

The favourable tolerance profile of donepezil is further complemented by its pharmacokinetic properties, characterised by a long plasma half-life (70 h), which is dose-independent (Rogers et al., 1992), and a similar disposition in young and elderly subjects (Ohnishi et al., 1993). The elimination of donepezil occurs slowly and through both renal excretion of intact drug and biotransformation via the cytochrome P450 system. Studies have shown that this balanced elimination pathway is not significantly influenced by either renal or hepatic disease (Rogers et al., 1997, Tiseo et al., 1997). Thus, there is no special patient population in which dosage adjustment is necessary.

It has been suggested that the treatment benefits produced by cholinesterase inhibitors are transient and that therapy beyond 1 year may not be justified. However, no data have been put forth to validate this suggestion. Controlled trials with placebo are not tenable for examining this issue due to ethical considerations and the fact that drop-out rates become significant in studies longer than 6 months. Thus, although not ideal, data from patients on extended treatment may be compared with similar data from untreated patient cohorts to evaluate the efficacy of donepezil over the long term.

Section snippets

Patients

Male and female patients aged 55 years and older with an established diagnosis of mild to moderately severe Alzheimer's disease (Diagnostic and Statistical Manual of Mental Disorders III-R Edition [American Psychiatric Association, 1987]; NINCDS [McKhann et al., 1984]), who had completed a previous randomised, double-blind, placebo-controlled trial of donepezil (1, 3, 5 mg/day) (Rogers et al., 1996b), were eligible for enrollment. All female patients were either surgically sterile or at least

Patients

Of the 161 patients entering the double-blind trial, 141 patients completed the trial and were eligible for the present open-label study. Of these, 133 patients (94%) enrolled and received open-label study treatment, 122 (92%) of whom completed the first 12 weeks of open-label therapy, and 39 (29%) who are continuing in the study having participated for more than 3.5 years. The demographic characteristics of the patient population are shown in Table 1.

The 91 patients who discontinued treatment

Discussion

One of the major criticisms of current clinical trial programmes for ChE inhibitors is their focus on short-term efficacy and failure to evaluate the long-term benefits to patients with Alzheimer's disease. This is of particular concern with existing agents, such as tacrine, where the risks of hepatotoxicity and peripheral side effects may outweigh any long-term clinical benefit.

Since Alzheimer's disease is progressive, the natural course can complicate assessment of long-term treatment effect.

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