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Comtan

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Comtan

Comtan

CLINICAL PHARMACOLOGY

Mechanism of Action

Entacapone is a selective and reversible inhibitor of catechol-O-methyltransferase (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 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 catechol-O-methyltransferase (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/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 h - 2.4 h. 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/carbidopa.

Pharmacokinetics of Entacapone

Entacapone pharmacokinetics are linear over the dose range of 5 mg - 800 mg, and are independent of levodopa/carbidopa coadministration. The elimination of entacapone is biphasic, with an elimination half-life of 0.4 h - 0.7 h based on the β-phase and 2.4 h based on the γ-phase. The γ-phase accounts for approximately 10% of the total AUC. The total body clearance after i.v. administration is 850 mL/min. After a single 200-mg dose of Comtan (entacapone), the Cmax is approximately 1.2 μg/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 i.v. 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 50 μg/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 trials was largely limited to Caucasians (there were only 4 blacks in one US trial and no Asians in any of the clinical trials); no conclusions can therefore be reached about the effect of Comtan (entacapone) on groups other than Caucasian.

Hepatic Impairment

A single 200-mg dose of entacapone, without levodopa/dopa decarboxylase inhibitor coadministration, showed approximately twofold 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 7 patients with liver disease had mild hepatic impairment and 3 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/dopa decarboxylase inhibitor coadministration, in a specific renal impairment study. There were three groups: normal subjects (n=7; creatinine clearance > 1.12 mL/sec/1.73 m²), moderate impairment (n=10; creatinine clearance ranging from 0.60 - 0.89 mL/sec/1.73 m²), and severe impairment (n=7; creatinine clearance ranging from 0.20 - 0.44 mL/sec/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 Comtan (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 trials in patients with Parkinson's Disease. In two of these trials, the patients' disease was “fluctuating”, i.e., was 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 trial patients were not required to have been experiencing fluctuations. Prior to the controlled part of the trials, patients were stabilized on levodopa for 2 - 4 weeks. Comtan (entacapone) has not been systematically evaluated in patients who do not experience 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/carbidopa (up to 10 times daily, but averaging 4-6 doses per day). The formal double-blind portion of both trials was 6 months long. Patients recorded the time spent in the “On” and “Off” states in home diaries periodically throughout the duration of the trial. 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 was evaluated, and patients were also evaluated by subparts of the Unified Parkinson's Disease Rating Scale (UPDRS), a frequently used multi-item rating scale intended to assess mentation (Part I), activities of daily living (Part II), motor function (Part III), complications of therapy (Part IV), and disease staging (Part V & VI); an 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/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/carbidopa or levodopa/benserazide). In the second trial, 205 patients were randomized in 17 centers in North America (US and Canada); all patients received concomitant levodopa/carbidopa.

The following tables display the results of these two trials:

Table 1: Nordic Study

Primary Measure from Home Diary (from an 18-hour Diary Day)
  Baseline Change from Baseline at Month 6* p-value vs. placebo
Hours of Awake Time “On”
  Placebo 9.2 +0.1
  Comtan 9.3 +1.5 < 0.001
Duration of “On” time after first AM dose (hrs)
  Placebo 2.2 0.0
  Comtan 2.1 +0.2 < 0.05
Secondary Measures from Home Diary (from an 18-hour Diary Day)
Hours of Awake Time “Off”
  Placebo 5.3 0.0
  Comtan 5.5 - 1.3 < 0.001
Proportion of Awake Time “On” *** (%)
  Placebo 63.8 +0.6
  Comtan 62.7 +9.3 < 0.001
Levodopa Total Daily Dose (mg)
  Placebo 705 +14
  Comtan 701 - 87 < 0.001
Frequency of Levodopa Daily Intakes
  Placebo 6.1 +0.1
  Comtan 6.2 - 0.4 < 0.001
Other Secondary Measures
  Baseline Change from Baseline at Month 6 p-value vs. placebo
Investigator's Global (overall) %
  Placebo 28
  Comtan 56 < 0.01
Patient's Global (overall)% Improved**
  Placebo 22
  Comtan 39 N.S.‡
UPDRS Total
  Placebo 37.4 -1.1
  Comtan 38.5 -4.8 < 0.01
UPDRS Motor
  Placebo 24.6 -0.7
  Comtan 25.5 -3.3 < 0.05
UPDRS ADL
  Placebo 11.0 -0.4
  Comtan 11.2 -1.8 < 0.05
* Mean; the month 6 values represent the average of weeks 8, 16, and 24, by protocol-defined outcome measure.
** At least one category change at endpoint.
*** Not an endpoint for this study but primary endpoint in the North American Study.
‡ Not significant.

Table 2: North American Study

Primary Measure from Home Diary (for a 24-hour Diary Day)
  Baseline Change from
Baseline at Month 6
p-value
vs. placebo
Percent of Awake Time “On”
  Placebo 60.8 +2.0
  Comtan 60.0 +6.7 < 0.05
Secondary Measures from Home Diary (for a 24-hour Diary Day)
Hours of Awake Time “Off”
  Placebo 6.6 - 0.3
  Comtan 6.8 - 1.2 < 0.01
Hours of Awake Time “On”
  Placebo 10.3 + 0.4
  Comtan 10.2 + 1.0 N.S.‡
Levodopa Total Daily Dose (mg)
  Placebo 758 + 19
  Comtan 804 - 93 <0.001
Frequency of Levodopa Daily Intakes
  Placebo 6.0 + 0.2
  Comtan 6.2 0.0 N.S.‡
Other Secondary Measures
  Baseline Change from Baseline at Month 6 p-value vs. placebo
Investigator's Global (overall) %
  Placebo 21
  Comtan 34 < 0.05
Patient's Global (overall) % Improved**
  Placebo 20
  Comtan 31 < 0.05
UPDRS Total***
  Placebo 35.6 +2.8
  Comtan 35.1 -0.6 < 0.05
UPDRS Motor***
  Placebo 22.6 +1.2
  Comtan 22.0 -0.9 < 0.05
UPDRS ADL***
  Placebo 11.7 +1.1
  Comtan 11.9 0.0 < 0.05
* Mean; the month 6 values represent the average of weeks 8, 16, and 24, by protocol-defined outcome measure.
** At least one category change at endpoint.
*** Score change at endpoint similarly to the Nordic Study.
‡ Not significant.

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/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 trial, a total of 301 patients were randomized in 32 centers in Germany and Austria. In this trial, as in the other two trials, entacapone 200 mg was administered with each dose of levodopa/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 seen for the primary measures, as well as for some secondary measures:

Table 3: German-Austrian Study

Primary Measures
  Baseline Change from Baseline at Month 6 p-value vs. placebo (LOCF)
UPDRS ADL*
  Placebo 12.0 +0.5
  Comtan 12.4 -0.4 < 0.05
UPDRS Motor*
  Placebo 24.1 +0.1
  Comtan 24.9 -2.5 < 0.05
Hours of Awake Time “On” (Home diary)**
  Placebo 10.1 +0.5
  Comtan 10.2 +1.1 N.S.‡
Secondary Measures
  Baseline Change from Baseline at Month 6 p-value vs. placebo
UPDRS Total*
  Placebo 37.7 +0.6
  Comtan 39.0 -3.4 < 0.05
Percent of Awake Time “On” (Home diary)**
  Placebo 59.8 +3.5
  Comtan 62.0 +6.5 N.S.‡
Hours of Awake Time “Off” (Home diary)**
  Placebo 6.8 -0.6
  Comtan 6.3 -1.2 0.07
Levodopa Total Daily Dose (mg)*
  Placebo 572 +4
  Comtan 566 -35 N.S.
Frequency of Levodopa Daily Intake*
  Placebo 5.6 +0.2
  Comtan 5.4 0.0 < 0.01
Global (overall) % Improved***
  Placebo 34
  Comtan 38 N.S.‡
* Total population; score change at endpoint.
** Fluctuating population, with 5-10 doses; score change at endpoint.
*** Total population; at least one category change at endpoint.
‡Not significant.

Last reviewed on RxList: 11/4/2010
This monograph has been modified to include the generic and brand name in many instances.

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