CLINICAL PHARMACOLOGY
Mechanism of Action
Tolcapone is a selective and reversible inhibitor of catechol- O -methyltransferase (COMT).
In mammals, COMT is distributed throughout various organs. The highest activities are 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, 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 precise mechanism of action of tolcapone is unknown, but it is believed to be related to its ability to inhibit COMT and alter the plasma pharmacokinetics of levodopa. When tolcapone is given in conjunction with levodopa and an aromatic amino acid decarboxylase inhibitor, such as carbidopa, plasma levels of levodopa are more sustained than after administration of levodopa and an aromatic amino acid decarboxylase inhibitor alone. It is believed that these 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 in patients as well as increased levodopa adverse effects, sometimes requiring a decrease in the dose of levodopa. Tolcapone enters the CNS to a minimal extent, but has been shown to inhibit central COMT activity in animals.
Pharmacodynamics
COMT Activity in Erythrocytes: Studies in healthy volunteers have shown that tolcapone reversibly inhibits human erythrocyte catechol- O -methyltransferase (COMT) activity after oral administration. The inhibition is closely related to plasma tolcapone concentrations. With a 200-mg single dose of tolcapone, maximum inhibition of erythrocyte COMT activity is on average greater than 80%. During multiple dosing with tolcapone (200 mg tid), erythrocyte COMT inhibition at trough tolcapone blood concentrations is 30% to 45%.
Effect on the Pharmacokinetics of Levodopa and its Metabolites
When tolcapone is administered together with levodopa/carbidopa, it increases the relative bioavailability (AUC) of levodopa by approximately twofold. This is due to a decrease in levodopa clearance resulting in a prolongation of the terminal elimination half-life of levodopa (from approximately 2 hours to 3.5 hours). In general, the average peak levodopa plasma concentration (Cmax) and the time of its occurrence (Tmax) are unaffected. The onset of effect occurs after the first administration and is maintained during long-term treatment. Studies in healthy volunteers and Parkinson’s disease patients have confirmed that the maximal effect occurs with 100 mg to 200 mg tolcapone. Plasma levels of 3-OMD are markedly and dose-dependently decreased by tolcapone when given with levodopa/carbidopa.
Population pharmacokinetic analyses in patients with Parkinson’s disease have shown the same effects of tolcapone on levodopa plasma concentrations that occur in healthy volunteers.
Pharmacokinetics of Tolcapone
Tolcapone pharmacokinetics are linear over the dose range of 50 mg to 400 mg, independent of levodopa/carbidopa coadministration. The elimination half-life of tolcapone is 2 to 3 hours and there is no significant accumulation. With tid dosing of 100 mg or 200 mg, Cmax is approximately 3 µg/mL and 6 µg/mL, respectively.
Absorption: Tolcapone is rapidly absorbed, with a Tmax of approximately 2 hours. The absolute bioavailability following oral administration is about 65%. Food given within 1 hour before and 2 hours after dosing of tolcapone decreases the relative bioavailability by 10% to 20% (see DOSAGE AND ADMINISTRATION).
Distribution: The steady-state volume of distribution of tolcapone is small (9 L). Tolcapone does not distribute widely into tissues due to its high plasma protein binding. The plasma protein binding of tolcapone is >99.9% over the concentration range of 0.32 to 210 µg/mL. In vitro experiments have shown that tolcapone binds mainly to serum albumin.
Metabolism and Elimination: Tolcapone is almost completely metabolized prior to excretion, with only a very small amount (0.5% of dose) found unchanged in urine. The main metabolic pathway of tolcapone is glucuronidation; the glucuronide conjugate is inactive. In addition, the compound is methylated by COMT to 3- O -methyl-tolcapone. Tolcapone is metabolized to a primary alcohol (hydroxylation of the methyl group), which is subsequently oxidized to the carboxylic acid. In vitro experiments suggest that the oxidation may be catalyzed by cytochrome P450 3A4 and P450 2A6. The reduction to an amine and subsequent N -acetylation occur to a minor extent. After oral administration of a 14C-labeled dose of tolcapone, 60% of labeled material is excreted in urine and 40% in feces. Tolcapone is a low-extraction-ratio drug (extraction ratio = 0.15) with a moderate systemic clearance of about 7 L/h.
Special Populations
Tolcapone pharmacokinetics are independent of sex, age, body weight, and race (Japanese, Black and Caucasian). Polymorphic metabolism is unlikely based on the metabolic pathways involved.
Hepatic Impairment: A study in patients with hepatic impairment has shown that moderate non-cirrhotic liver disease had no impact on the pharmacokinetics of tolcapone. In patients with moderate cirrhotic liver disease (Child-Pugh Class B), however, clearance and volume of distribution of unbound tolcapone was reduced by almost 50%. This reduction may increase the average concentration of unbound drug by twofold (see DOSAGE AND ADMINISTRATION). TASMAR therapy should not be initiated if the patient exhibits clinical evidence of active liver disease or two SGPT/ALT or SGOT/AST values greater than the upper limit of normal (see BOXED WARNING).
Renal Impairment: The pharmacokinetics of tolcapone have not been investigated in a specific renal impairment study. However, the relationship of renal function and tolcapone pharmacokinetics has been investigated using population pharmacokinetics during clinical trials. The data of more than 400 patients have confirmed that over a wide range of creatinine clearance values (30 mL/min to 130 mL/min) the pharmacokinetics of tolcapone are unaffected by renal function. This could be explained by the fact that only a negligible amount of unchanged tolcapone (0.5%) is excreted in the urine. The glucuronide conjugate of tolcapone is mainly excreted in the urine but is also excreted in the bile. Accumulation of this stable and inactive metabolite should not present a risk in renally impaired patients with creatinine clearance above 25 mL/min (see DOSAGE AND ADMINISTRATION). Given the very high protein binding of tolcapone, no significant removal of the drug by hemodialysis would be expected.
Drug Interactions: See PRECAUTIONS: Drug Interactions.
Clinical Studies
The effectiveness of TASMAR as an adjunct to levodopa in the treatment of Parkinson’s disease was established in three multicenter randomized controlled trials of 13 to 26 weeks’ duration, supported by four 6-week trials whose results were consistent with those of the longer trials. In two of the longer trials, tolcapone was evaluated in patients whose Parkinson’s disease was characterized by deterioration in their response to levodopa at the end of a dosing interval (so-called fluctuating patients with wearing-off phenomena). In the remaining trial, tolcapone was evaluated in patients whose response to levodopa was relatively stable (so-called non-fluctuators).
Fluctuating Patients: In two 3-month trials, patients with documented episodes of wearing-off phenomena, despite optimum levodopa therapy, were randomized to receive placebo, tolcapone 100 mg tid or 200 mg tid. The formal double-blind portion of the trial was 3 months long, and the primary outcome was a comparison between treatments in the change from baseline in the amount of time spent “On” (a period of relatively good functioning) and “Off” (a period of relatively poor functioning). Patients recorded periodically, throughout the duration of the trial, the time spent in each of these states.
In addition to the primary outcome, patients were also assessed using sub-parts of the Unified Parkinson’s Disease Rating Scale (UPDRS), a frequently used multi-item rating scale intended to evaluate mentation (Part I), activities of daily living (Part II), motor function (Part III), complications of therapy (Part IV), and disease staging (Parts V and VI); an Investigator’s Global Assessment of Change (IGA), a subjective scale designed to assess global functioning in 5 areas of Parkinson’s disease; the Sickness Impact Profile (SIP), a multi-item scale in 12 domains designed to assess the patient’s functioning in multiple areas; and the change in daily levodopa/carbidopa dose.
In one of the studies, 202 patients were randomized in 11 centers in the United States and Canada. In this trial, all patients were receiving concomitant levodopa and carbidopa. In the second trial, 177 patients were randomized in 24 centers in Europe. In this trial, all patients were receiving concomitant levodopa and benserazide.
The following tables display the results of these 2 trials:
Table 1. US/Canadian Fluctuator Study | Primary Measure |
| Baseline | Change from Baseline | |
| (hrs) | at Month 3 (hrs) | p-value* |
| * Compared to placebo. |
| ** Hours “Off” or “On” are based on the percent of waking day “Off” or “On”, assuming a 16-hour waking day. |
| Hours of Wake Time “Off ” ** | | | |
| Placebo | 6.2 | -1.2 | – |
| 100 mg tid | 6.4 | -2.0 | 0.169 |
| 200 mg tid | 5.9 | -3.0 | <0.001 |
| Hours of Wake Time “On” ** | | | |
| Placebo | 8.7 | 1.4 | – |
| 100 mg tid | 8.1 | 2.0 | 0.267 |
| 200 mg tid | 9.1 | 2.9 | 0.008 |
| Secondary Measures |
| Baseline | Change from Baseline | |
| | at Month 3 | p-value* |
| Levodopa Total Daily Dose (mg) | | | |
| Placebo | 948 | 16 | – |
| 100 mg tid | 788 | -166 | <0.001 |
| 200 mg tid | 865 | -207 | <0.001 |
| Global (overall) % Improved | | | |
| Placebo | – | 42 | – |
| 100 mg tid | – | 71 | <0.001 |
| 200 mg tid | – | 91 | <0.001 |
| UPDRS Motor | | | |
| Placebo | 19.5 | -0.4 | – |
| 100 mg tid | 17.6 | -1.9 | 0.217 |
| 200 mg tid | 20.6 | -2.0 | 0.210 |
| UPDRS ADL | | | |
| Placebo | 7.5 | -0.3 | – |
| 100 mg tid | 7.7 | -0.8 | 0.487 |
| 200 mg tid | 8.3 | 0.2 | 0.412 |
| SIP (total) | | | |
| Placebo | 14.7 | -2.2 | – |
| 100 mg tid | 14.9 | -0.4 | 0.210 |
| 200 mg tid | 17.6 | -0.3 | 0.216 |
Table 2. European Fluctuator Study | Primary Measure |
| * Compared to placebo. |
| ** Hours “Off” or “On” are based on the percent of waking day “Off” or “On”, assuming a 16-hour waking day. |
| Effects on “Off” time and levodopa dose did not differ by age or sex. |
| Baseline | Change from Baseline | |
| (hrs) | at Month 3 (hrs) | p-value* |
| Hours of Wake Time “Off ” ** | | | |
| Placebo | 6.1 | -0.7 | – |
| 100 mg tid | 6.5 | -2.0 | 0.008 |
| 200 mg tid | 6.0 | -1.6 | 0.081 |
| Hours of Wake Time “On” ** | | | |
| Placebo | 8.5 | -0.1 | – |
| 100 mg tid | 8.1 | 1.7 | 0.003 |
| 200 mg tid | 8.4 | 1.7 | 0.003 |
| Secondary Measures |
| Baseline | Change from Baseline | |
| | at Month 3 | p-value* |
| Levodopa Total Daily Dose (mg) | | | |
| Placebo | 660 | -29 | – |
| 100 mg tid | 667 | -109 | 0.025 |
| 200 mg tid | 675 | -122 | 0.010 |
| Global (overall) % Improved | | | |
| Placebo | – | 37 | – |
| 100 mg tid | – | 70 | 0.003 |
| 200 mg tid | – | 78 | <0.001 |
| UPDRS Motor | | | |
| Placebo | 24.0 | -2.1 | – |
| 100 mg tid | 22.4 | -4.2 | 0.163 |
| 200 mg tid | 22.4 | -6.5 | 0.004 |
| UPDRS ADL | | | |
| Placebo | 7.9 | -0.5 | – |
| 100 mg tid | 7.5 | -0.9 | 0.408 |
| 200 mg tid | 7.7 | -1.3 | 0.097 |
| SIP (total) | | | |
| Placebo | 21.6 | -0.9 | – |
| 100 mg tid | 16.6 | -1.9 | 0.419 |
| 200 mg tid | 18.4 | -4.2 | 0.011 |
Non-fluctuating Patients: In this study, 298 patients with idiopathic Parkinson’s disease on stable doses of levodopa/carbidopa who were not experiencing wearing-off phenomena were randomized to placebo, tolcapone 100 mg tid, or tolcapone 200 mg tid for 6 months at 20 centers in the United States and Canada. The primary measure of effectiveness was the Activities of Daily Living portion (Subscale II) of the UPDRS. In addition, the change in daily levodopa dose, other subscales of the UPDRS, and the SIP were assessed as secondary measures. The results are displayed in the following table:
Table 3. US/Canadian Non-fluctuator Study | Primary Measure |
| *Compared to placebo. |
| Effects on Activities of Daily Living did not differ by age or sex. |
| Baseline | Change from Baseline | |
| | at Month 6 | p-value* |
| UPDRS ADL | | | |
| Placebo | 8.5 | 0.1 | – |
| 100 mg tid | 7.5 | -1.4 | <0.001 |
| 200 mg tid | 7.9 | -1.6 | <0.001 |
| Secondary Measures |
| Baseline | Change from Baseline | |
| | at Month 6 | p-value* |
| Levodopa Total Daily Dose (mg) | | | |
| Placebo | 364 | 47 | – |
| 100 mg tid | 370 | -21 | <0.001 |
| 200 mg tid | 381 | -32 | <0.001 |
| UPDRS Motor | | | |
| Placebo | 19.7 | 0.1 | – |
| 100 mg tid | 17.3 | -2.0 | 0.018 |
| 200 mg tid | 16.0 | -2.3 | 0.008 |
| SIP (total) | | | |
| Placebo | 6.9 | 0.4 | – |
| 100 mg tid | 7.3 | -0.9 | 0.044 |
| 200 mg tid | 7.3 | -0.7 | 0.078 |
| Percent of Patients who | | | |
| Developed Fluctuations | | | |
| Placebo | – | 26 | – |
| 100 mg tid | – | 19 | 0.297 |
| 200 mg tid | – | 14 | 0.047 |
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