Entacapone …

K K Jain MD†

Neuropharmacology & Neurotherapeutics

Updated 09.04.2021
Released 11.09.1999
Expires For CME 09.04.2024

Entacapone

Author: K K Jain MD†

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Entacapone

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Introduction

Historical note and terminology

Since its demonstration of effectiveness against Parkinson disease in 1961, levodopa has become the mainstay therapy for this disease. However, most of the orally administered levodopa is converted by catechol-O-methyltransferase into the inactive metabolite 3-O-methyldopa before crossing the blood-brain barrier. The accumulated 3-O-methyldopa then competes with levodopa for the saturable neutral amino acid active transport system in the gut and the blood vessel wall leading to motor fluctuations. The object of catechol-O-methyltransferase inhibitors such as entacapone and tolcapone is to inhibit the action of this enzyme.

Catechol-O-methyltransferase was found to be widely distributed in human tissues such as the glia (05). Catechol-O-methyltransferase inhibition was subsequently shown to lower the circulating levels of 3-O-methyldopa and improve the bioavailability of levodopa. The first-generation nonselective catechol-O-methyltransferase inhibiting drugs were studied but abandoned in the 1970s because of toxicity and lack of efficacy. The second-generation catechol-O-methyltransferase inhibitors, which were developed in the late 1980s, include entacapone and tolcapone. Both of these are reversible catechol-O-methyltransferase inhibitors and are in clinical trials. Both compounds have also been approved. Entacapone acts mainly peripherally, whereas tolcapone acts both peripherally and centrally. Entacapone was approved in the European Union in 1998 and by the United States Food and Drug Administration in 1999. A levodopa/carbidopa/entacapone combination product (Stalevo) was approved in 2003 to treat patients with idiopathic Parkinson disease who experience end-of-dose “wearing-off.”

Pharmacology

Pharmacodynamics.

Entacapone (chemical structure)

(Contributed by Dr. K K Jain.)

Entacapone inhibits catechol-O-methyltransferase in a dose-dependent, reversible, and tight-binding manner but does not affect other catechol metabolizing enzymes. It enables the reduction of levodopa dose. Catechol-O-methyltransferase inhibitors may influence the response to levodopa in Parkinson disease by the following mechanisms:

	• Catechol-O-methyltransferase in the gut may metabolize levodopa during absorption and, thus, reduce the bioavailability of the drug.
	• O-methylation of levodopa in the systemic circulation can facilitate the elimination of levodopa from plasma and, thus, reduce the plasma half-life of levodopa.
	• O-methylation of levodopa by catechol-O-methyltransferase in the brain capillary endothelial cells further reduces the entry of levodopa into the brain.
	• O-methylation of dopamine terminates the action of the neurotransmitter in the brain.

Catechol-O-methyltransferase inhibitors substantially increase the levels of free 18F-dopa in the plasma and the striatum after their administration. Catechol-O-methyltransferase inhibitors act effectively and safely to increase the amount of levodopa that is available to enter the brain by extending the half-life of levodopa, resulting in more stable levels in the plasma and prolonging "on" time. Repeated dosing of entacapone inhibits the catechol-O-methyltransferase activity in a dose-dependent manner and thereby reduces the loss of levodopa to 3-O-methyldopa, leading to improvement in the patients' clinical condition. Entacapone enhances the clinical efficacy of controlled-release levodopa formulations and is of value in extending the benefits of levodopa in Parkinson disease patients experiencing motor fluctuations. Entacapone significantly increases the bioavailability of levodopa and reduces its daily variation by 25% when administered concomitantly with a controlled-release levodopa preparation.

Peripherally acting entacapone, unlike the centrally acting tolcapone, is a safer catechol-O-methyltransferase inhibitor for the treatment of Parkinson disease because it does not interfere with mitochondrial energy metabolism at pharmacologically effective concentrations. Entacapone administration as an adjunct produces a greater reduction in homocysteine in levodopa-induced hyperhomocysteinemia when associated with low folate levels in patients with Parkinson disease.

In patients with levodopa-resistant “freezing of gait,” coadministration entacapone with L-threo-3,4-dihydroxyphenylserine, a precursor of noradrenaline, is proposed as a strategy for treatment (04).

Opicapone is another catechol-o-methyl transferase inhibitor that has the advantage of being administered once daily and has pharmacokinetic data to indicate it offers a greater degree of catechol-o-methyl transferase inhibition than entacapone.

Pharmacokinetics. Important pharmacokinetic features of entacapone include:

	• Entacapone is rapidly absorbed after oral administration, and mean maximum plasma concentrations of 1160 to 1500 µg are reached within 0.7 to 1.3 hours after a single dose of 200 mg in patients with Parkinson disease.
	• Half-life of oral entacapone is 1 to 2 hours.
	• The Z-isomer of entacapone is the main metabolite in human plasma. The Z-isomer is approximately 5% of the total area under the curve of both isomers.
	• Systemic bioavailability is approximately 36% following an oral dose of 200 mg in healthy volunteers.
	• About 10% of the oral dose of entacapone is excreted in the urine within 8 hours.
	• Entacapone, in combination with levodopa or dopa decarboxylase inhibitor, increases the area under the curve of levodopa, which leads to less fluctuation of levodopa plasma concentrations.

Therapeutic drug monitoring. A liquid chromatography with ultraviolet light-based method has been shown to be reliable, practical, and cost-effective for the quantification of entacapone in human plasma (03).

Effect of different formulations of controlled-release entacapone on pharmacokinetics. Single-dose pharmacokinetics of extended-release carbidopa-levodopa (CD-LD) versus immediate-release CD-LD, sustained-release CD-LD, and CD-LD-entacapone in healthy subjects showed that bioavailability of LD from extended-release CD-LD was 83.5%, 78.3%, and 58.8% relative to immediate CD-LD, controlled-release CD-LD, and CD-LD-entacapone, respectively (06). A systematic review of randomized clinical trials showed that entacapone administered in combination with levodopa in a single tablet resulted in a better quality of life compared to separate tablets (11). Levodopa-entacapone-carbidopa intestinal gel provides continuous drug delivery through intrajejunal infusion and results in a 36.5% lower levodopa clearance, thereby lowering continuous maintenance doses regardless of patients' COMT genotype (12).

Pharmacogenomics. A randomized controlled clinical trial provides class II evidence that an increased dose of carbidopa improves motor fluctuations in Parkinson disease, ie, daily "off" times, when administered with levodopa and entacapone (NCT01766258). These improvements were seen in patients with high-activity COMT genotypes; therefore, genotyping patients with Parkinson disease according to COMT activity may improve individual treatment strategies (15).

Clinical trials

Since the 1990s, several clinical trials of entacapone have been conducted on patients with Parkinson disease who had an end-of-dose deterioration in response to levodopa. Results of published studies have shown that treatment with entacapone is associated with significant daily increases in “on” time and decreases in “off” time. Entacapone improved total activities of daily living and motor function scores, but it had no effect on mentation scores. In smaller trials, entacapone also provided benefits when given with controlled-release levodopa and aromatic-L-amino acid decarboxylase inhibitor or with standard levodopa and aromatic-L-amino acid decarboxylase inhibitor and selegiline. A few examples of clinical trials of entacapone during the past decade are given.

A prospective 134-week double-blind trial randomized Parkinson disease patients to receive levodopa/carbidopa or levodopa/carbidopa/entacapone (13). Initiation of levodopa therapy with levodopa/carbidopa/entacapone failed to delay the time of onset or reduce the frequency of dyskinesia compared to levodopa/carbidopa.

A double-blind randomized trial compared perampanel, a selective and noncompetitive glutamate receptor antagonist, with placebo and entacapone in levodopa-treated Parkinson disease patients with “off” problems (10). Perampanel did not have a clinically significant effect in improving motor symptoms of levodopa-treated patients, but these patients responded to the active comparator, entacapone.

A retrospective, pooled analysis of 4 phase 3 randomized, double-blind, placebo-controlled trials with entacapone showed that it improved daily “off” and “on” times compared with placebo and was generally well tolerated (07).

A metaanalysis of various studies has shown that entacapone used as adjuvant therapy to levodopa is effective in the management of Parkinson disease with fluctuations, but patients on entacapone had a higher frequency of adverse events (none were severe) than those on placebo (08).

A metaanalysis and systematic review of randomized trials has shown that levodopa/carbidopa/entacapone combination is more effective than levodopa/dopa-decarboxylase inhibitor for the treatment of Parkinson disease by improving scores in UPDRS II and UPDRS III scales (16).

References

01: Alshammari TM, AlMutairi EN. Use of an entacapone-containing drug combination and risk of death: Analysis of the FDA AERS (FAERS) database. Saudi Pharm J 2015;23(1):28-32.** PMID 25685040
02: Baldacci F, Vergallo A, Del Dotto P, et al. Occurrence of Takotsubo syndrome in a patient with Parkinson's disease after entacapone add-on. Parkinsonism Relat Disord 2014;20(11):1313-4. PMID 25258328
03: Belal F, Ibrahim F, Sheribah ZA, Alaa H. Micellar HPLC-UV method for the simultaneous determination of levodopa, carbidopa and entacapone in pharmaceuticals and human plasma. J Chromatogr B Analyt Technol Biomed Life Sci 2018;1091:36-45. PMID 29843067
04: Fukada K, Endo T, Yokoe M, Hamasaki T, Hazama T, Sakoda S. L-threo-3,4-dihydroxyphenylserine (L-DOPS) co-administered with entacapone improves freezing of gait in Parkinson's disease. Med Hypotheses 2013;80(2):209-12. PMID 23265352
05: Guldberg HC, Marsden CA. Catechol-O-methyltransferase: pharmacological aspects and physiological role. Pharmacol Rev 1975;27:135-206. PMID 1103160
06: Hsu A, Yao HM, Gupta S, Modi NB. Comparison of the pharmacokinetics of an oral extended-release capsule formulation of carbidopa-levodopa (IPX066) with immediate-release carbidopa-levodopa (Sinemet(®)), sustained-release carbidopa-levodopa (Sinemet(®) CR), and carbidopa-levodopa-entacapone (Stalevo(®)). J Clin Pharmacol 2015;55(9):995-1003. PMID 25855267
07: Kuoppamaki M, Vahteristo M, Ellmen J, Kieburtz K. Pooled analysis of phase III with entacapone in Parkinson's disease. Acta Neurol Scand 2014;130(4):239-47.** PMID 25186800
08: Li J, Lou Z, Liu X, Sun Y, Chen J. Efficacy and safety of adjuvant treatment with entacapone in advanced Parkinson's disease with motor fluctuation: a systematic meta-analysis. Eur Neurol 2017;78(3-4):143-53.** PMID 28813703
09: Major JM, Dong D, Cunningham F, et al. Entacapone and prostate cancer in Parkinson's disease patients: A large Veterans Affairs healthcare system study. Parkinsonism Relat Disord 2018;53:46-52. PMID 29759929
10: Rascol O, Barone P, Behari M, et al. Perampanel in Parkinson disease fluctuations: a double-blind randomized trial with placebo and entacapone. Clin Neuropharmacol 2012;35(1):15-20. PMID 22222634
11: Salamon A, Zádori D, Szpisjak L, Klivényi P, Vécsei L. Fixed-dose combination therapy for Parkinson's disease with a spotlight on entacapone in the past 20 years: a reduced pill burden and a simplified dosing regime. Expert Opin Pharmacother 2020;1-14.** PMID 32808807
12: Senek M, Nyholm D, Nielsen EI. Population pharmacokinetics of levodopa gel infusion in Parkinson's disease: effects of entacapone infusion and genetic polymorphism. Sci Rep 2020;10(1):18057.** PMID 33093598
13: Stocchi F, Rascol O, Kieburtz K, et al. Initiating levodopa/carbidopa therapy with and without entacapone in early Parkinson disease: the STRIDE-PD study. Ann Neurol 2010;68(1):18-27. PMID 20582993
14: Tambasco N, Muti M, Chiarini P, et al. Entacapone reduces cortical activation in Parkinson's disease with wearing-off: a f-MRI study. PLoS One 2014;9(5):e96806. PMID 24830331
15: Trenkwalder C, Kuoppamäki M, Vahteristo M, Müller T, Ellmén J. Increased dose of carbidopa with levodopa and entacapone improves "off" time in a randomized trial. Neurology 2019;92(13):e1487-96. PMID 30824559
16: Yi ZM, Qiu TT, Zhang Y, Liu N, Zhai SD. Levodopa/carbidopa/entacapone versus levodopa/dopa-decarboxyiase inhibitor for the treatment of Parkinson's disease: systematic review, meta-analysis, and economic evaluation. Ther Clin Risk Manag 2018;14:709-19. PMID 29713179
17: Yoo DY, Jung HY, Kim W, et al. Entacapone treatment modulates hippocampal proteins related to synaptic vehicle trafficking. Cells 2020;9(12):2712. PMID 33352833

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Entacapone

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Entacapone …

Entacapone

Introduction

Historical note and terminology

Pharmacology

Pharmacodynamics.

Clinical trials

Indications

Off-label uses

Contraindications

Goals and duration of treatment

Dosing

Special considerations

Interactions

Adverse effects

Media

References

Contributors

Author

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Questions or Comment?

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Entacapone

Introduction

Historical note and terminology

Pharmacology

Pharmacodynamics.

Clinical trials

Indications

Off-label uses

Contraindications

Goals and duration of treatment

Dosing

Special considerations

Interactions

Adverse effects

Media

References

Contributors

Author

This is an article preview. Start a Free Account to access the full version.

Questions or Comment?

Also in This Category

Hemifacial spasm

Wilson disease

Acupuncture

Neuroacanthocytosis

Restless legs syndrome

Dementia in Parkinson disease

ALS-like disorders of the Western Pacific

Illicit drug use: neurologic complications

This is an article preview.
Start a Free Account
to access the full version.