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Galantamine

A Review of its Use in Alzheimer’s Disease

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Summary

Abstract

Currently, acetylcholinesterase (AChE) inhibitors are the most promising class of drugs for the treatment of Alzheimer’s disease (AD). Galantamine is a reversible, competitive, tertiary alkaloid AChE inhibitor. The drug is selective for AChE rather than butyrylcholinesterase. In addition to inhibition of AChE galantamine interacts allosterically with nicotinic acetylcholine receptors to potentiate the action of agonists at these receptors.

Recipients of galantamine 16 or 24 mg/day achieved significant improvements in cognitive and global symptoms relative to placebo recipients in large (n = 285 to 978 patients with mild to moderate AD) well-designed trials of 3 to 6 months’ duration. Galantamine also improved activities of daily living in these patients and significantly reduced the requirement for caregiver assistance with activities of daily living. Moreover, galantamine recipients achieved significantly better outcomes on behavioural symptoms than placebo recipients.

In a long term study (12 months), galantamine 24 mg/day slowed the progression of symptoms of the disease and maintained cognitive function and activities of daily living in patients with mild to moderate AD.

Galantamine was generally well tolerated with the majority of adverse events being mild to moderate in intensity and transient. Predictably, adverse events were cholinergic in nature and generally related to the gastrointestinal system. These effects were reduced in patients receiving the recommended dose escalation regimen. Galantamine had no clinically relevant effects on vital signs, haematological or biochemical laboratory parameters and, importantly, there were no reports of hepatotoxicity. The incidence of serious adverse events was similar between galantamine (8 to 32 mg/day) and placebo groups (6 to 16% of patients across all treatment groups).

Conclusions: Galantamine is an effective well tolerated symptomatic treatment for AD which improves cognition, function and activities of daily living in the short term (up to 6 months) in patients with mild to moderate AD. In addition, it delays the development of behavioural disturbances and psychiatric symptoms, and reduces caregiver burden (as measured by caregiver time). In the long term (up to 1 year), galantamine maintains cognition and activities of daily living. Adverse events associated with galantamine are mainly cholinergic, usually mild to moderate in intensity and transient. Galantamine has been evaluated in several large well-designed studies and, given the relative lack of established treatment options, it may be considered as one of the first-line pharmacological treatments in patients with mild to moderate AD.

Pharmacodynamic Profile

Galantamine, a tertiary alkaloid, is a selective, competitive inhibitor of acetylcholinesterase (AChE). The inhibitor affinity (Ki) of galantamine for AChE in rat striatal tissue was 0.015 μmol/L. In postmortem brain tissue from patients without evidence of psychiatric disorder and fresh cortical brain biopsies from patients undergoing neurosurgery, galantamine inhibited AChE activity in a concentration-dependent manner. In postmortem samples, the concentrations of drug required to inhibit AChE activity by 50% were 3.2 and 2.8 μmol/L for the frontal cortex and hippocampal region, respectively. Tacrine and physostigmine exhibited a higher degree of AChE inhibition than galantamine in these regions of the brain. Galantamine was 10-fold less potent at inhibiting AChE from fresh brain cortex biopsies than from erythrocytes, whereas tacrine exhibited similar enzymatic inhibition levels in tissue from both sources.

In 5 patients with possible or probable Alzheimer’s disease (AD) receiving oral galantamine 5mg 3 times daily for 2 to 3 months, erythrocyte AChE activity was inhibited by 21 to 41% 2 hours after the morning dose. Recovery of AChE activity occurred within ≈30 hours of the final dose of the drug. There was no detectable inhibition of butyrylcholinesterase in galantamine-treated patients for the duration of the study.

Galantamine selectively inhibited AChE rather than butyrylcholinesterase in human plasma and erythrocytes. The drug showed a 53-fold selectivity for AChE over butyrylcholinesterase.

In addition to inhibition of AChE, galantamine interacts directly with nicotinic acetylcholine receptors (nAChRs) and potentiates their action. Galantamine binds allosterically to the α-subunit of nAChRs. In cultured cell lines expressing nAChRs, galantamine modulated ion channel activity and potentiated the actions of the receptors in the presence of agonists.

Galantamine attenuated drug- and lesion-induced cognitive deficits in animal models of learning and memory. The beneficial effects of galantamine on scopolamine-induced deficit in rats were similar to those observed with tacrine.

Pharmacokinetic Profile

Galantamine is rapidly absorbed following oral administration. Mean maximum plasma drug concentrations (Cmax) after a single oral (tablet) 10mg dose ranged considerably from 49.2 to 1150 μg/L and were reached in a mean of 0.88 or 2 hours in healthy volunteers in 2 studies. At steady state, mean Cmax and trough plasma concentrations (Cmin) of galantamine fluctuated between 42 to 137 μg/L and 29 to 97 μg/L, respectively, following 12 or 16mg twice daily doses. In clinical trials, Cmax values were 30 to 40% higher in patients with AD than those observed in healthy young volunteers. The mean absolute oral bioavailability of galantamine was 100% in healthy volunteers.

Galantamine has a large volume of distribution following oral administration, confirming the high non-specific absorption of this drug. Although intravenous administration of galantamine in mice resulted in a rapid accumulation of the drug in tissues, patients receiving 12 or 16mg twice daily showed no evidence of accumulation of the drug after 2 to 6 months of therapy. Plasma protein binding of galantamine is low (18%).

The major route of metabolism of galantamine is via cytochrome (CYP) P450 isoenzymes (mainly CYP2D6 and CYP3A4) in the liver, with ≈75% of a galantamine dose metabolised. After intravenous or oral administration 18 to 22% of the dose is excreted unchanged in the urine during the first 24 hours. Seven days after a single oral radiolabelled 4mg galantamine dose 90 to 97% of the radioactivity had been recovered in the urine compared with 2.2 to 6.3% in the faeces. Galantamine is metabolised to several compounds and although some of these metabolites inhibit AChE in vitro, their activity in vivo is not considered clinically relevant. In vitro studies have shown that galantamine has a low potential to inhibit the major forms of CYP isoenzymes.

Galantamine demonstrates biexponential elimination, with a mean plasma terminal elimination half-life (t½β) of 5.26 to 5.68 hours in healthy volunteers. In patients with AD the typical oral clearance is 12 L/h, with an interindividual variability in oral clearance of 30%. Renal clearance of galantamine in healthy volunteers after oral administration represented 20 to 25% of total plasma clearance.

Since galantamine acts by inhibiting acetylcholinesterase, interactions with drugs that have an effect on the cholinergic system could be expected. When administered in combination with agents that significantly reduce the heart rate (e.g. digoxin and β-blockers), a pharmacodynamic interaction is possible. Furthermore, galantamine is likely to potentiate the action of succinylcholine on muscle relaxation during anaesthesia. In addition, potent inhibitors of CYP3A4 and CYP2D6 may potentiate the cholinergic effects of galantamine.

Clinical Efficacy

Galantamine has been evaluated in large (n = 285 to 978), well-designed trials of 3 to 6 months’ duration in patients with mild to moderate AD, as well as in several small nonblind studies. Galantamine 16 or 24 mg/day demonstrated efficacy at 3 to 6 months across all studies, with significant differences from placebo observed for all primary and most secondary efficacy assessment measures when intention-to-treat last observation carried forward (LOCF) analysis was performed at the end of the double-blind study period.

Galantamine-treated patients showed significant improvements in cognition, behavioural symptoms and activities of daily living compared with placebo recipients. These beneficial effects of galantamine therapy on cognition and activities of daily living were achieved regardless of the apolipoprotein E ε4 allele count [assessed using the cognitive (11 item) subscale of the Alzheimer’s Disease Assessment Scale (ADAS-cog/11) and Disability Assessment in Dementia (DAD) scores]. The mean decrease (improvement) from baseline in the ADAS-cog/11 scores in these patients was 0.6 to 1.9 points compared with an increase (deterioration) of 0.6 to 2.2 points in the placebo group. Overall, Clinician Interview-Based Impression of Change with Caregiver Input (CIBIC-plus) outcomes were significantly (p < 0.05 all comparisons) better in galantamine than placebo recipients. Clinically meaningful improvements of ≥4 points in ADAS-cog/11 scores were observed in more galantamine (16 to 32 mg/day) recipients (33.3 to 37% of patients) than placebo recipients (16.6 and 19.6%) in two 5- and 6-month studies (p < 0.01 all comparisons within each study). Activities of daily living outcomes were also significantly better in these galantamine-treated patients than in placebo recipients, with benefits in both basic and instrumental DAD cluster scores. Furthermore, galantamine recipients showed markedly better outcomes for behavioural symptoms than placebo recipients, as measured using the Neuropsychiatric Inventory, with galantamine treatment delaying the development of behavioural disturbances and psychiatric symptoms.

Long term evaluation indicated that galantamine 24 mg/day maintained cognition and activities of daily living in patients who had received this dose throughout a 12-month study period (6 months’ double-blind, then a 6-month extension where the investigators remained blinded to treatment in the double-blind phase). ADAS-cog/11 and DAD scores were maintained relative to baseline levels in these galantamine-treated patients. Patients from the other double-blind groups (galantamine 32 mg/day or placebo), who received galantamine 24 mg/day in the extension phase, experienced a deterioration in these scores. During the 6-month extension phase, a similar proportion of patients (54 to 61%) from each of the previous double-blind treatment groups remained stable or improved according to CIBIC-plus scores.

Galantamine reduced the requirement for caregiver input compared with placebo. In a 6-month study, galantamine 24 or 32 mg/day recipients showed no significant change from baseline in the requirement for caregiver supervision compared with an additional 2 hours of supervision per day required by placebo recipients at 6 months (p < 0.001 vs baseline). There was also a decrease in the time caregivers spent assisting galantamine recipients with activities of daily living (≤38 minutes/day) compared with a significant increase of 23 minutes/day from baseline in the placebo group. On-treatment analysis indicates that galantamine treatment reduces caregiver distress arising from the behavioural symptoms of the patient.

Tolerability

Galantamine was generally well tolerated in patients with AD. Adverse events were generally those expected from an AChE inhibitor. The overall incidence of adverse events appeared to be similar between galantamine 8, 16 or 24 mg/day and placebo groups (73.8 to 80.2% vs 72 to 78.9% of patients). Although a high proportion of galantamine recipients experienced at least 1 adverse event, these events were usually mild to moderate in severity, transient and generally occurred during the dose titration phase. Adverse effects were reduced in patients receiving the recommended dose escalation regimen. In general, a similar proportion of patients discontinued treatment due to adverse events in the galantamine and placebo groups in double-blind trials of 3 to 6 months’ duration.

The most common adverse events occurring at least 5% more frequently in galantamine (16 to 24 mg/day) than placebo recipients were nausea, vomiting, diarrhoea and anorexia. The proportion of serious adverse events was similar between galantamine (8 to 32 mg/day) and placebo groups (6 to 16% of patients across treatment groups; nature of events not reported). Notably, the incidence of muscle weakness in galantamine recipients was similar to that observed in the placebo group (0.4 to 1.1% vs 1% of patients). According to the manufacturer’s summary of product information, there was no difference in the incidence of seizures in clinical trials in galantamine recipients compared with placebo recipients. Galantamine had no clinically relevant effects on vital signs or haemato-logical or biochemical laboratory parameters and, importantly, no hepatooxicity was observed.

Galantamine treatment is associated with a slight, but in one study significant, bodyweight loss. The mean decrease in bodyweight with galantamine 8, 16 and 24 mg/day was 0.5, 0.5 and 1.3kg, respectively, compared with a decrease of 0.1kg in the placebo group. Patients experiencing a decrease in mean bodyweight generally had higher baseline bodyweights (>50kg in women and >70kg in men).

Evaluation of 218 patients who completed 1 year of treatment with galantamine 24 mg/day indicated that the most common adverse events during the 6-month extension phase were nausea, vomiting, dizziness, diarrhoea, anorexia, abdominal pain and tremor. The overall incidence of adverse events during the extension phase was 85.3% compared with 78.9% during the double-blind phase, with 16% of patients withdrawing during the extension phase. During the extension phase, galantamine recipients appeared to recover some of the weight lost during the 6-month double-blind phase.

Dosage and Administration

In Europe, galantamine is recommended for use in adult patients with mild to moderate dementia of the AD type. The drug should be administered orally twice daily, preferably with morning and evening meals. The recommended starting dosage is 8 mg/day for 4 weeks. The initial maintenance dosage is 16 mg/day for at least 4 weeks. After this time, an increase to the recommended maintenance dosage of 24 mg/day should be considered on an individual basis after assessment of clinical benefit and tolerability.

Galantamine is contraindicated in patients with severe hepatic (Child Pugh score >9) and/or renal (creatinine clearance <0.54 L/h) impairment. In patients with moderate hepatic impairment, treatment should be initiated at a dosage of 4mg once daily (preferably taken with the morning meal). After 4 weeks, the dosage may be increased to 4mg twice daily with a minimum of 4 weeks at this dosage. After this time, the dosage may be increased further to a maximum dosage of 8mg twice daily. There is no requirement for dosage adjustment in patients with mild hepatic impairment or in those with a creatine clearance ≥0.54 L/h.

Agents that inhibit cholinesterase may augment the activity of succinylcholine and other muscle relaxants, have vagotonic effects on heart rate and may have the potential to cause generalised seizures. These agents, including galantamine, should be used with care in patients with a history of asthma or obstructive pulmonary disease, and monitoring is recommended when they are used in patients at risk of developing ulcers. Galantamine is not recommended in patients with a gastrointestinal or a urinary outflow obstruction or in those recovering from bladder or gastrointestinal surgery. In patients receiving concomitant CYP3A4 or CYP2D6 inhibitors dosage reductions of galantamine may be required.

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Correspondence to Lesley J. Scott.

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Various sections of the manuscript reviewed by: A. Burns, University of Manchester, Manchester, England; M.R. Farlow, Indiana University School of Medicine, Indianapolis, Indiana, USA; E. Giacobini, University of Geneva Medical School, Geneva, Switzerland; C-G. Gottfries, Goteborg University, Institute of Clinical Neuroscience, Goteborg, Sweden; F.H. McDowell, Winifred Masterton Burke Rehabilitation Hospital, White Plains, New York, USA; A.Maelicke, Johannes-Gutenberg University Medical School, Mainz, Germany; A. Nordberg, Karolinska Institute, Huddinge University Hospital, Huddinge, Sweden.

Data Selection

Sources: Medical literature published in any language since 1966 on Galantamine, identified using AdisBase (a proprietary database of Adis International, Auckland, New Zealand), Medline and EMBASE. Additional references were identified from the reference lists of published articles. Bibliographical information, including contributory unpublished data, was also requested from the company developing the drug.

Search strategy: AdisBase search terms were ‘Galantamine’ or ‘galanthamine’ or ‘GP-37267’. Medline search terms were ‘Galantamine’ or ‘galanthamine’ or ‘GP-37267’ or ‘357-70-0’. EMBASE search terms were ‘Galantamine’ or ‘galanthamine’ or 357-70-0’. Searches were last updated 28 Aug 2000.

Selection: Studies in patients with mild to moderate Alzheimer’s Disease who received galantamine. Inclusion of studies was based mainly on the methods section of the trials. When available, large, well controlled trials with appropriate statistical methodology were preferred. Relevant pharmacodynamic and pharmacokinetic data are also included.

Index terms: Galantamine, Alzheimer’s disease, acetylcholinesterase inhibitor, pharmacodynamics, pharmacokinetics, therapeutic use.

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Scott, L.J., Goa, K.L. Galantamine. Drugs 60, 1095–1122 (2000). https://doi.org/10.2165/00003495-200060050-00008

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