Mechanism of Action

Entacapone is a selective and reversible inhibitor of COMT.

In mammals, COMT is distributed throughout various organs with the highest activities in the liver and kidney. COMT also occurs in the heart, lung, smooth and skeletal muscles, intestinal tract, reproductive organs, various glands, adipose tissue, skin, blood cells and neuronal tissues, especially in glial cells. COMT catalyzes the transfer of the methyl group of S-adenosyl-L-methionine to the phenolic group of substrates that contain a catechol structure. Physiological substrates of COMT include dopa, catecholamines (dopamine, norepinephrine and epinephrine) and their hydroxylated metabolites. The function of COMT is the elimination of biologically active catechols and some other hydroxylated metabolites. In the presence of a decarboxylase inhibitor, COMT becomes the major metabolizing enzyme for levodopa, catalyzing the metabolism to 3-methoxy-4-hydroxy-L-phenylalanine (3-OMD) in the brain and periphery.

The mechanism of action of entacapone is believed to be through its ability to inhibit COMT and alter the plasma pharmacokinetics of levodopa. When entacapone is given in conjunction with levodopa and an aromatic amino acid decarboxylase inhibitor, such as carbidopa, plasma levels of levodopa are greater and more sustained than after administration of levodopa and an aromatic amino acid decarboxylase inhibitor alone. It is believed that at a given frequency of levodopa administration, these more sustained plasma levels of levodopa result in more constant dopaminergic stimulation in the brain, leading to greater effects on the signs and symptoms of Parkinson’s disease. The higher levodopa levels also lead to increased levodopa adverse effects, sometimes requiring a decrease in the dose of levodopa.

In animals, while entacapone enters the central nervous system (CNS) to a minimal extent, it has been shown to inhibit central COMT activity. In humans, entacapone inhibits the COMT enzyme in peripheral tissues. The effects of entacapone on central COMT activity in humans have not been studied.

Pharmacodynamics

COMT Activity in Erythrocytes: Studies in healthy volunteers have shown that entacapone reversibly inhibits human erythrocyte COMT activity after oral administration. There was a linear correlation between entacapone dose and erythrocyte COMT inhibition, the maximum inhibition being 82% following an 800 mg single dose. With a 200 mg single dose of entacapone, maximum inhibition of erythrocyte COMT activity is on average 65% with a return to baseline level within 8 hours.

Effect on the Pharmacokinetics of Levodopa and its Metabolites

When 200 mg entacapone is administered together with levodopa and carbidopa, it increases the area under the curve (AUC) of levodopa by approximately 35%, and the elimination half-life of levodopa is prolonged from 1.3 hours to 2.4 hours. In general, the average peak levodopa plasma concentration and the time of its occurrence (Tmax of 1 hour) are unaffected. The onset of effect occurs after the first administration and is maintained during long-term treatment. Studies in Parkinson’s disease patients suggest that the maximal effect occurs with 200 mg entacapone. Plasma levels of 3-OMD are markedly and dose-dependently decreased by entacapone when given with levodopa and carbidopa.

Pharmacokinetics of Entacapone

Entacapone pharmacokinetics are linear over the dose range of 5 mg to 800 mg, and are independent of levodopa and carbidopa coadministration. The elimination of entacapone is biphasic, with an elimination half-life of 0.4 hour to 0.7 hour based on the β-phase and 2.4 hours based on the γ-phase. The γ-phase accounts for approximately 10% of the total AUC. The total body clearance after intravenous administration is 850 mL per min. After a single 200 mg dose of entacapone, the Cmax is approximately 1.2 mcg per mL.

Absorption: Entacapone is rapidly absorbed, with a Tmax of approximately 1 hour. The absolute bioavailability following oral administration is 35%. Food does not affect the pharmacokinetics of entacapone.

Distribution: The volume of distribution of entacapone at steady state after intravenous injection is small (20 L). Entacapone does not distribute widely into tissues due to its high plasma protein binding. Based on in vitro studies, the plasma protein binding of entacapone is 98% over the concentration range of 0.4 mcg per mL to 50 mcg per mL. Entacapone binds mainly to serum albumin.

Metabolism and Elimination: Entacapone is almost completely metabolized prior to excretion, with only a very small amount (0.2% of dose) found unchanged in urine. The main metabolic pathway is isomerization to the cis-isomer, followed by direct glucuronidation of the parent and cis-isomer; the glucuronide conjugate is inactive. After oral administration of a 14C-labeled dose of entacapone, 10% of labeled parent and metabolite is excreted in urine and 90% in feces.

Special Populations: Entacapone pharmacokinetics are independent of age. No formal gender studies have been conducted. Racial representation in clinical studies was largely limited to Caucasians; therefore, no conclusions can be reached about the effect of entacapone on groups other than Caucasian.

Hepatic Impairment: A single 200 mg dose of entacapone, without levodopa and dopa decarboxylase inhibitor coadministration, showed approximately 2-fold higher AUC and Cmax values in patients with a history of alcoholism and hepatic impairment (n=10) compared to normal subjects (n=10). All patients had biopsy-proven liver cirrhosis caused by alcohol. According to Child-Pugh grading seven patients with liver disease had mild hepatic impairment and three patients had moderate hepatic impairment. As only about 10% of the entacapone dose is excreted in urine as parent compound and conjugated glucuronide, biliary excretion appears to be the major route of excretion of this drug. Consequently, entacapone should be administered with care to patients with biliary obstruction.

Renal Impairment: The pharmacokinetics of entacapone have been investigated after a single 200 mg entacapone dose, without levodopa and dopa decarboxylase inhibitor coadministration, in a specific renal impairment study. There were three groups: normal subjects (n=7; creatinine clearance greater than 1.12 mL per sec per 1.73 m2), moderate impairment (n=10; creatinine clearance ranging from 0.60 mL per sec per 1.73 m2 to 0.89 mL per sec per 1.73 m2) and severe impairment (n=7; creatinine clearance ranging from 0.20 mL per sec per 1.73 m2 to 0.44 mL per sec per 1.73 m2). No important effects of renal function on the pharmacokinetics of entacapone were found.

Drug Interactions: See PRECAUTIONS, Drug Interactions.

Clinical Studies

The effectiveness of entacapone as an adjunct to levodopa in the treatment of Parkinson’s disease was established in three 24-week multicenter, randomized, double-blind, placebo-controlled studies in patients with Parkinson’s disease. In two of these studies, patients had motor “fluctuations”, characterized by documented periods of “On” (periods of relatively good functioning) and “Off” (periods of relatively poor functioning), despite optimum levodopa therapy. There was also a withdrawal period following 6 months of treatment. In the third study, patients were not required to have motor fluctuations. Prior to the controlled part of the studies, patients were stabilized on levodopa for 2 weeks to 4 weeks. Entacapone has not been systematically evaluated in patients who have Parkinson’s disease without motor fluctuations.

In the first two studies to be described, patients were randomized to receive placebo or entacapone 200 mg administered concomitantly with each dose of levodopa and carbidopa (up to 10 times daily, but averaging 4 doses to 6 doses per day). The formal double-blind portion of both studies was 6 months long. Patients recorded the time spent in the “On” and “Off” states in home diaries periodically throughout the duration of the study. In one study, conducted in the Nordic countries, the primary outcome measure was the total mean time spent in the “On” state during an 18-hour diary recorded day (6 AM to midnight). In the other study, the primary outcome measure was the proportion of awake time spent over 24 hours in the “On” state.

In addition to the primary outcome measure: the amount of time spent in the “Off” state, subparts of the Unified Parkinson’s Disease Rating Scale (UPDRS) including mentation (Part I), activities of daily living (ADL) (Part II), motor function (Part III), complications of therapy (Part IV) and disease staging (Part V and VI) were assessed. Additional secondary endpoints included the investigator’s and patient’s global assessment of clinical condition, a 7-point subjective scale designed to assess global functioning in Parkinson’s disease; and the change in daily levodopa and carbidopa dose.

In one of the studies, 171 patients were randomized in 16 centers in Finland, Norway, Sweden and Denmark (Nordic study), all of whom received concomitant levodopa plus dopa-decarboxylase inhibitor (either levodopa and carbidopa or levodopa and benserazide). In the second study, 205 patients were randomized in 17 centers in North America (US and Canada); all patients received concomitant levodopa and carbidopa.

The following tables display the results of these two studies:

     * Mean; the month 6 values represent the average of weeks 8, 16 and 24, by protocol-defined outcome measure, except for Investigator's and Patient's Global Improvement.
     † At least one category change at endpoint.
     ‡ Not an endpoint for this study but primary endpoint in the North American Study.
     § Not significant. 
     ¶ P-values for Secondary Measures and Other Secondary Measures are nominal P values without any adjustment for multiplicity. 

    * Mean; the month 6 values represent the average of weeks 8, 16 and 24, by protocol-defined outcome measure, except for Investigator's and Patient's Global Improvement.
     † At least one category change at endpoint. 
     ‡ Score change at endpoint similarly to the Nordic Study. 
     § Not significant.

¶ P-values for Secondary Measures and Other Secondary Measures are nominal P values without any adjustment for multiplicity.

Effects on “On” time did not differ by age, sex, weight, disease severity at baseline, levodopa dose and concurrent treatment with dopamine agonists or selegiline.

Withdrawal of entacapone: In the North American study, abrupt withdrawal of entacapone, without alteration of the dose of levodopa and carbidopa, resulted in a significant worsening of fluctuations, compared to placebo. In some cases, symptoms were slightly worse than at baseline, but returned to approximately baseline severity within two weeks following levodopa dose increase on average by 80 mg. In the Nordic study, similarly, a significant worsening of parkinsonian symptoms was observed after entacapone withdrawal, as assessed two weeks after drug withdrawal. At this phase, the symptoms were approximately at baseline severity following levodopa dose increase by about 50 mg.

In the third placebo-controlled study, a total of 301 patients were randomized in 32 centers in Germany and Austria. In this study, as in the other two studies, entacapone 200 mg was administered with each dose of levodopa and dopa decarboxylase inhibitor (up to 10 times daily) and UPDRS Parts II and III and total daily “On” time were the primary measures of effectiveness. The following results were observed for the primary measures, as well as for some secondary measures: