, Volume 58, Issue 1, pp 159–177 | Cite as


A Review of its Use in Parkinson’s Disease
  • Kristin J. Holm
  • Caroline M. Spencer
Adis Drug Evaluation



Entacapone is a potent and specific peripheral catechol-O-methyltransferase (COMT) inhibitor. It has been shown to improve the clinical benefits of levodopa plus an aromatic L-amino acid decarboxylase inhibitor (AADC) when given to patients with Parkinson’s disease and end-of-dose deterioration in the response to levodopa (the ‘wearing off’ phenomenon). The efficacy of entacapone is currently being assessed in patients with stable Parkinson’s disease.

In 2 well conducted trials of 6 months’ duration and smaller short term studies, treatment with entacapone (200mg with each dose of levodopa/AADC inhibitor) was associated with significant increases in daily ‘on’ time and decreases in ‘off’ time. Changes in Unified Parkinson’s Disease Rating Scale (UPDRS) scores concurred with changes in ‘on’ and ‘off’ times: entacapone improved total, activities of daily living and motor function scores, but it had no effect on mentation scores. Entacapone also provided benefits when given with controlled release levodopa/ AADC inhibitor or with standard levodopa/AADC inhibitor and selegiline in small trials.

Dopaminergic events, including dyskinesia and nausea, are among the most common events with entacapone, and are related to the drug’s ability to potentiate the effects of levodopa. Diarrhoea, abdominal pain, constipation and urine discolouration are the most common nondopaminergic events, although the latter event is the only one to occur consistently more frequently with entacapone than with placebo. However, adverse events of any type infrequently led to study discontinuation.

Conclusions: The efficacy and tolerability of entacapone administered with levodopa/AADC inhibitor have not yet been compared with those of other strategies for the treatment of Parkinson’s disease. However, once the decision to initiate levodopa therapy has been made, studies generally support the use of entacapone as an adjunct to levodopa in patients with Parkinson’s disease and the ‘wearing off’ phenomenon.

Pharmacodynamic Properties

Results of in vitro and ex vivo studies indicate that entacapone is a potent, specific, reversible and peripherally acting soluble catechol-O-methyltransferase (COMT) inhibitor. The drug has activity against COMT at a number of peripheral sites, but does not alter cerebral COMT activity in vivo at doses used clinically. Entacapone does not affect other enzymes that metabolise catecholamines.

Inhibition of COMT activity reduces peripheral degradation of levodopa and increases central levodopa, and therefore dopamine, concentrations. In positron emission tomography studies using fluorodopa (an analogue of levodopa), single doses of entacapone have significantly increased unmetabolised fluorodopa fractions in both patients with Parkinson’s disease and in healthy volunteers.

Coadministration of entacapone with levodopa plus an aromatic L-amino acid decarboxylase inhibitor (AADC) potentiates the effects of levodopa in patients with Parkinson’s disease and reduces the ‘wearing off’ phenomenon (see Therapeutic Efficacy and Tolerability summaries). Potentiation of the effects of levodopa by entacapone has also been shown in animals.

Therapeutic doses of entacapone have only small effects on epinephrine (adrenaline) and norepinephrine (noradrenaline) levels at rest or during exercise in healthy volunteers or patients with Parkinson’s disease; both catecholamines are primarily metabolically inactivated by COMT and monoamine oxidase (MAO). However, the pattern of metabolism of these agents is altered: plasma 3,4-dihydroxyphenylglycol and 3,4-dihydroxyphenylacetic acid levels are increased and plasma 3-methoxy-4-hydroxyphenylglycol levels are decreased. Compared with either monotherapy, when entacapone and the MAO-A inhibitor moclobemide are coadministered, similar or smaller changes in levels of the catecholamines and their metabolites are observed.

Few haemodynamic changes are reported after administration of entacapone to healthy volunteers or patients with Parkinson’s disease.


Entacapone is rapidly absorbed after oral administration of a single dose, and mean maximum plasma concentration (Cmax) of 1160 to 1500 μg/L are generally reached 0.7 to 1.3 hours after administration of a 200mg dose in patients with Parkinson’s disease. Importantly, no accumulation of plasma entacapone was detected in healthy male volunteers who received 8 daily doses of entacapone 200mg for 5 days.

The elimination of entacapone is mainly described by 2 phases; the β-phase represents approximately 90% of elimination and the γ-phase about 10%. The β-phase elimination half-life (t½β) of entacapone after IV administration is 0.5 to 0.7 hours and the y-phase half-life (t½γ) is 2.4 to 3.5 hours. Additional data indicate that the t½ of oral entacapone 200mg is 1 to 2 hours, which is similar to the t½ of levodopa (≈1.7 hours).

The mean oral bioavailability of entacapone 200mg was 36% in healthy volunteers.

The Z-isomer of entacapone is the main metabolite of entacapone (itself the E-isomer) in human plasma. The area under the plasma concentration-time curve (AUC) of the Z-isomer is approximately 5% of the total AUC of both isomers. About 10% of an oral entacapone dose is excreted into the urine within 8 hours. Entacapone is primarily eliminated via biliary excretion in humans.

Impairment of liver function (alcoholic cirrhosis) significantly increases the bioavailability of entacapone 200mg. The pharmacokinetic parameters of single doses of entacapone are not affected in patients with renal failure or in the elderly.

Single doses of entacapone 50 to 200mg and repeated entacapone doses (for 7 days to 8 weeks) dose dependently increase the AUC and elimination half-life (t½) of levodopa when coadministered with levodopa/AADC inhibitor; no further increases are seen with entacapone 400mg. However, Cmaxand time to reach Cmax (tmax) values for levodopa are generally unaffected by entacapone. Eight weeks’ treatment with entacapone increases mean levodopa concentrations, interdose trough concentrations and interdose peak concentrations in patients with Parkin-son’s disease, but no accumulation of levodopa occurs. AUC values of the levo-dopa metabolite 3-O-methyldopa are reduced by entacapone.

Tmax and Cmax values for levodopa were increased to a greater extent when repeated doses of entacapone (600 to 800 mg/day for 10 days) were given with controlled release levodopa/carbidopa than when the drug was administered with standard levodopa/carbidopa.

Improved clinical effects of levodopa significantly and positively correlated with increased AUC values of plasma levodopa after coadministration with single doses of entacapone versus levodopa alone.

Therapeutic Efficacy

The efficacy of entacapone in patients with Parkinson’s disease has been assessed only in patients with an end-of-dose deterioration in the response to levodopa (the ‘wearing off’ phenomenon) to date. The largest trials to have assessed the efficacy of entacapone in patients with Parkinson’s disease are 2 multicentre double-blind randomised placebo-controlled 6-month studies, conducted in North America (n = 205) and Scandinavia (n = 171). In all trials, entacapone 200mg was administered with each dose of levodopa/carbidopa or levodopa/benserazide.

The duration of daily ‘on’ time improves by up to 2.1 hours when oral entacapone is administered with standard levodopa/AADC inhibitor. In the large 6-month trials, entacapone improved the duration of daily ‘on’ time by 1 to 1.2 hours. Entacapone has shown efficacy after the first dose.

In 1 study, entacapone had a significant treatment effect in patients who had a low proportion of ‘on’ time at baseline (<55% of the awake day), but not in those who spent ≥55% of their awake day ‘on’. The benefits of the drug were noted to increase over the day.

Patients’ daily ‘off’ time was reduced to a significantly greater extent in entacapone (1.3 hours) than in placebo (0.1 hours) recipients during treatment in 1 double-blind trial. Changes in UPDRS scores concur with changes in ‘on’ and ‘off’ times, and entacapone significantly improves total, activities of daily living and motor function scores but it has no effect on mentation scores versus placebo or baseline. Investigators’ global assessments rated entacapone superior to placebo in patients receiving levodopa/AADC inhibitor.

Mean daily levodopa dosages were reduced from baseline by 11 to 16% in recipients of entacapone and levodopa/AADC inhibitor compared with in those receiving levodopa/AADC inhibitor alone.

The beneficial effects of entacapone are reversed rapidly after therapy withdrawal.

The benefits of entacapone were also observed when the drug was administered with controlled release levodopa/carbidopa or with standard levodopa/AADC inhibitor plus selegiline in patients with Parkinson’s disease, although data are limited.


Dopaminergic adverse events, including dyskinesia, nausea, dizziness, hallucinations, vomiting and insomnia, occurred with entacapone therapy in large clinical trials. These dopaminergic events probably occur because of increased plasma and brain levodopa levels.

Dyskinesia is among the most frequent adverse events in entacapone recipients. Dyskinesia occurs significantly more commonly with entacapone than with placebo and it almost always arises during the initial weeks of entacapone treatment. The incidence of dyskinesia is reduced after reduction of levodopa dosages.

Nausea is significantly more common in patients receiving entacapone than in those receiving placebo, however, it infrequently leads to treatment withdrawal.

Urine discolouration, diarrhoea, abdominal pain and constipation are the most common nondopaminergic adverse events to occur in entacapone recipients, although urine discolouration is the only event to occur consistently more frequently with entacapone than with placebo.

Entacapone generally causes no significant changes in haematological or biochemical parameters. Phase III studies assessed liver enzyme levels with entacapone and no association between the drug and liver toxicity was shown: the incidence of significant liver enzyme abnormalities (elevated alanine aminotrans-ferase or aspartate aminotransferase) was 0.8% in both entacapone and placebo recipients. Data from larger patient numbers are required to confirm these findings, and such studies are ongoing.

Similarly, there were no differences between entacapone and placebo groups in patients’ vital signs or ECG results in 2 large clinical trials.

Overall, dyskinesia and diarrhoea appear to be the most common reasons for stopping therapy in patients receiving entacapone for 6 to 12 months. However, the overall frequency of patient withdrawal from clinical trials because of adverse events was low, and was similar in entacapone and placebo recipients (5 to 7%).

Drug Interactions

In general, entacapone did not alter the metabolism of exogenously administered catecholamines nor, when administered with a MAO inhibitor or imipramine, did it potentiate cardiovascular changes.

Dosage and Administration

Entacapone is indicated for the treatment of patients with Parkinson’s disease and the ‘wearing off’ phenomenon. It is recommended that a dose of 200mg is taken with each daily dose of levodopa/AADC inhibitor. The maximum daily recommended dose of entacapone is 2000 mg/day.


Levodopa Selegiline Entacapone Tolcapone Carbidopa 
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Copyright information

© Adis International Limited 1999

Authors and Affiliations

  1. 1.Adis International LimitedMairangi Bay, AucklandNew Zealand

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