What Is Tolcapone?

Tocapone is a selective and reversible catechol-O-methyltransferase (COMT) inhibitor. It is clinically used as an adjuvant treatment for primary Parkinson's disease in combination with levodopa and carbidopa.

Basic Information

Chinese name: Tocapone

Chinese alias: tocapone; (3,4-dihydroxy-5-nitrophenyl)-(4-methylphenyl) methanone

Chemical Structure:

English name: Tolcapone

CAS NO: 53583-79-2

Molecular formula: C14H11NO5

Molecular weight: 273.24 ^[1]

Tocapone Tocapone-related drug labeling information

Drug Name:

[Common name] Tocapone

[English name] Tolcapone Tablets

[Chinese Pinyin] Tuo Ka Peng Pian

Tocapone ingredients

The main ingredient of this product is tocapone.

Tocapone traits

This product is a colored film-coated tablet, which is yellow after removing the coating.

Tocapone specifications

100mg / tablet

Tocapone dosage

oral. The recommended dose is 100 mg three times a day. As a superposition of levodopa / carbidopa treatment.
Tocapone tablets are taken orally three times a day. The first dose during the day should be taken at the same time as the first dose of the levodopa preparation during the day, and then it should be taken about 6 and 12 hours later. Tocapone can be taken with or without food. It can be used in combination with L-Dopa / Carbidopa's regular and sustained release dosage forms.
In clinical trials, most patients need to reduce their daily levodopa dose if their daily levodopa dose exceeds 600 mg or if they have moderate or severe dyskinesias before treatment begins.
Patients with liver function or kidney damage:
Due to the danger of liver damage caused by taking this product, any patients with liver disease should not take this product. Therefore, the patient's SGPT / ALT or SGOT / AST should not exceed the upper limit of normal values or other abnormal changes in liver function when starting this product.
No dosage adjustment is required for patients with mild or moderate renal impairment. Patients with severe renal impairment should use this product with extreme caution. Tocopene safety in patients with creatinine clearance below 25 mg / min has not been established.

Tocapone adverse reactions

According to foreign clinical research data:
1. Serious adverse events related to tocapone after listing.
Hepatocyte damage has been reported in post-market applications, including cases of death due to fulminant liver failure. In October 1998, three of the nearly 60,000 patients who took tocapone had fatal fulminant hepatic failure, and about 40,000 patients took tocapone every year worldwide. Its incidence is about 10-100 times higher than that of the general population. The problem of increased liver damage caused by taking tocapone cannot be ignored.
2. Adverse events found in pre-market clinical studies. (It is not clear whether the adverse events listed below have a causal relationship with taking tocapone.) The adverse events found in randomized double-blind and placebo-controlled clinical studies are as follows: Adverse events with a incidence of> 5% are: movement disorders , Nausea, sleep disorders, dystonia, dreaming, anorexia, muscle pain cramps, upright discomfort, drowsiness, diarrhea, insanity, dizziness, headache, hallucinations, vomiting, constipation, fatigue, upper respiratory infections, collapse, Sweating, urinary tract infection, dry mouth, abdominal pain, discoloration of urine. Below are arranged by each system.
(The incidence of common events is greater than 1/100; the incidence of occasional events is 1/100 to 1/1000; the incidence of rare events is less than 1/1000).
Nervous system-common: depression, anxiety, drowsiness, decreased sensation, tremor, speech impairment, dizziness, emotional instability; occasional: neuralgia, memory loss (amnesia), extrapyramidal symptoms, hostility, increased libido, mania Reaction, neurosensitivity, paranoid paranoid reaction, cerebral ischemia, cerebrovascular accident, delusion, hyposexuality, neuropathy, apathy, chorea, hand and foot asthma, myoclonus, psychosis, abnormal thinking, convulsions; rare: personality Metamorphosis, forgetfulness, encephalopathy, hemiplegia, meningitis.
Digestive system-common: dental diseases; occasional: dysphagia, gastrointestinal bleeding, gastroenteritis, oral ulcers, increased salivation, abnormal stool, esophagitis, gallstone disease, colitis, tongue disease, rectal disease; rare: Cholecystitis, duodenal ulcer, gastrointestinal tumor, lack of gastric tension.
Systemic diseases-common: pain in the flank, accidental injury, abdominal pain, infection, weakness, weight loss; occasional: hernia, pain, allergic reaction, peak fossa, fungal infection, viral infection, cancer, chill, bacterial infection, Vegetation, abscess, facial edema, rare: death.
Cardiovascular system-common: palpitations; occasional: hypertension, vasodilation, angina pectoris, heart failure, atrial fibrillation, tachycardia, migraine, aortic stenosis, arrhythmia, arterial spasm, bradycardia, cerebral hemorrhage, Coronary artery disease, cardiac arrest, myocardial infarction, myocardial ischemia, pulmonary embolism; occasional: arteriosclerosis, cardiovascular disease, pericardial effusion, thrombosis.
Musculoskeletal system-common: myalgia, arthralgia, limb pain, fractures; occasional: tenosynovitis, arthritis, joint disease.
Urogenital system-common: dripping urine, impotence; occasional: prostate disease, dysuria, nocturia, frequent urination, urinary retention, uterine relaxation, uterine disease, vaginitis. Rare: bladder stones, ovarian cancer, uterine bleeding.
Respiratory system-common: bronchitis, pharyngitis, pneumonia; occasional: increased cough, rhinitis, asthma, epistaxis, respiratory alkalosis, laryngitis, hiccup; rare: asphyxia, hypoxia, pulmonary edema.
Skin and appendages-common: rash. Occasionally: shingles, pruritus, seborrheic dermatitis, skin discoloration, eczema, erythema polymorpha, skin disease, rickets, herpes simplex, urticaria.
Special sensations-common: tinnitus, blue vision, sinusitis; occasional: diplopia, ear pain, eye bleeding, eye pain, tearing disorders, otitis media, olfactory sense; rare: glaucoma.
Metabolism and Nutrition-Common: Edema, hypercholesterolemia, thirst, dehydration.
Blood and Lymphatic System-Common: Anemia; Rare: Leukemia, Thrombocytopenia.
Endocrine system-occasional: diabetes.
Unclassified-common: surgery.

Tocapone taboo

1. Patients with liver disease and patients whose current SGPT / ALT or SGOT / AST exceeds the upper limit of normal value are prohibited from using this product;
2. Patients with severe renal impairment should not use this product;
3. People who are allergic to tocapone and any other ingredients in this product are prohibited from using this product;
4. This product is contraindicated in patients with a history of non-traumatic rhabdomyolysis;
5. Patients who have had fever and confusion in some disease states are prohibited from using this product;
6. Tokapone tablets should not be used in combination with non-selective monoamine oxidase inhibitors (such as phenelzine and tranylcypromine).
7. When taking tocapone, monoamine oxidase A inhibitor and monoamine oxidase B inhibitor should not be added at the same time.

Tocapone notes

Liver function: According to foreign literature reports, tocapone has been found to cause severe, fatal, and acute liver cell damage in clinical applications after being marketed abroad. Therefore, patients who choose to be treated with tocapone tablets Be extremely cautious. Before starting the medication, first check the patient's serum SGPT / ALT and SGOT / AST to determine the basic level, and then check the SGPT / ALT and SGOT / AST every two weeks during the first year of treatment. Checked every 4 weeks and thereafter every 8 weeks. If you exceed the normal upper limit or clinical symptoms and signs of liver damage (persistent nausea, fatigue, anorexia, jaundice, deeper urine color, itching, and right upper quadrant discomfort, etc.), the drug should be stopped immediately.

Hypotension / syncope: Tocapone can increase the bioavailability of levodopa and therefore increase the incidence of orthostatic hypotension, which requires attention. Particular caution should be exercised in patients with a history of hypotension / syncope. Patients should not quickly raise their posture from a sitting or lying position, especially if they have been in this posture for a long time, and they cannot change their posture quickly to prevent syncope.

Diarrhea: Different degrees of diarrhea may occur after taking tocapone, usually 6 to 12 weeks after taking the drug, but some patients may also be early or delayed. Patients with moderate to severe diarrhea during medication should be discontinued.

Hallucinations: Hallucinations may occur in patients taking tocapone and should be monitored. Once hallucinations occur, improvement can be achieved by reducing the amount of levodopa. If there is still no significant improvement, the drug should be discontinued.

Dyskinesia, decreased muscle tone, nausea, and other levodopa-related adverse reactions: When taking tocapone, patients will experience increased levodopa-related adverse reactions. These adverse reactions tend to be alleviated when the dose of levodopa is reduced.

If tocapone is discontinued, doctors should consider increasing the daily dose of levodopa to prevent the occurrence of neurosuppressive malignant syndrome.

Discoloration of urine: Tocapone and its metabolites are yellow, which can cause harmless deepening of urine color in patients.

During the taking of tocapone tablets, there may be a decrease in response. Do not drive or operate complex machines.

Tocapone medication for pregnant and lactating women

At present, there are no sufficient clinical research data of tocapone for pregnant women. Therefore, the safety and effectiveness of tocapone during pregnancy are not clear and should not be used.
Animal experiments have shown that tocapone tablets can be secreted into breast milk. Therefore, breastfeeding women should stop breastfeeding if they need to take it.

Tocapone children's medication

There is no evidence that tocapone tablets can be used in pediatric patients.

Tocapone medication for the elderly

See Dosage and Administration.

Tocapone drug interactions

Protein-binding rate: Although tocapone has a high protein-binding rate, in vitro studies have shown that the therapeutic concentration of tocapone (50 g / ml) does not displace from the binding sites of other drugs with higher protein-binding capacity. Drugs that have been tested include: warfarin (benzylacetone coumarin 0.5 to 7.2 g / ml), phenytoin (4.0 to 38.7 g / ml), tolbutamide (methatinine 24.5 to 96.1 g / ml) And digoxin (9.0-27.0 g / ml).
Tocapone, a drug metabolized by COMT, can affect the pharmacokinetics of a drug metabolized by COMT. However, the pharmacokinetics of the COMT substrate carbidopa was not affected. The effects of tocapone on other drugs of this type, such as alpha-methyl dobutamine, apomorphine, and isoprenaline, have not been evaluated. Consideration should be given to reducing the dose of these drugs when used in combination with tocapone.
Effects of tocapone on metabolism of other drugs In vitro tests have evaluated the possibility of tocapone interacting with the isomerase of cytochrome P450 (CYP).
Tocapone and CYP2A6 (warfarin coumadin) CYT 1A2 (caffeine), CYP3A4 (midazolam midazolam terfenadine terhenadine cyclosprine), CYP2C19 (S-mephengtoin) and CYP2D6 (in Interaction between substrates of mepromazine (desipramine). Tocapone does not interact with norpromazine, a drug metabolized by cytochrome P4502D6, which also confirms the results of in vivo experiments that tocapone does not alter the pharmacokinetics of norpromazine .
Due to the in vitro affinity of tocapone with cytochrome P450 2C9, it may interfere with drugs that clear metabolic pathways, such as metinin and warfarin. However, in vivo interaction studies have confirmed that tocapone does not Change the pharmacokinetics of metinin. Therefore, there seems to be no interaction between tocapone and cytochrome P4502C9. Similarly, tocapone does not affect the pharmacokinetics of normipramine, a drug metabolized by cytochrome P450 2D6, suggesting that tocapone and There is no interaction between drugs that rely on P450 2D6 metabolism. In view of the limited clinical data of warfarin combined with tocapone, coagulation parameters should be monitored when the two drugs are combined.
Medications that increase catechol No matter during rest or exercise, tocapone does not affect the effects of ephedrine (a direct sympathomimetic) and does not change its hemodynamic parameters or plasma catechol levels. Carpenter does not change the tolerance of ephedrine, and the two drugs can be combined.
When tocapone was used in combination with levodopa, carbidopa, and norpromazine, its blood pressure, pulse rate, and norpromazine plasma concentration did not change significantly. The frequency of adverse reactions increased slightly. Based on the respective adverse reactions of the three drugs, their total adverse reactions can be predicted. Therefore, norpromazine should be used with caution in patients with Parkinson's disease who are receiving tocapone and levodopa / carbidopa.
In clinical trials, patients who are receiving a tocapone / levodopa formulation, whether or not they are taking selegiline (a selective MAO-inhibitor), have also reported a similar profile of adverse effects.

Tocapone overdose

Once overdose occurs, the patient may have various manifestations such as nausea, vomiting, and dizziness. No specific antagonist of tocapone has been found. For its overdose, symptomatic and supportive treatment should be carried out according to the conventional treatment principles of overdose. Hemodialysis may be ineffective.

Tocapone pharmacology and toxicology

Pharmacological effects:

Tocapone is a selective and reversible catechol-O-methyltransferase (COMT) inhibitor. The function of COMT is to remove biologically active catechol and other hydroxyl metabolites. In the presence of a decarboxylase inhibitor, COMT converts brain and peripheral zodopa into 3-methyl-4-hydroxy-L-benzene The main metabolic enzyme of alanine (3-OMD). The exact mechanism of action of tocapone is unknown, but it is likely related to its inhibition of COMT and changes in the plasma pharmacokinetics of zotodopa. When tocapone is used in combination with zodopa and aromatic amino acid decarboxylase inhibitors (such as carbidopa), plasma zodopa levels are lower than when zodopa and aromatic amino acid decarboxylase inhibitors are used alone It can be maintained for a longer period of time, which may lead to more durable dopaminergic activation in the brain, which will have a stronger alleviating effect on the signs and symptoms of Parkinson's patients, and increase the adverse effects of zotodopa. Dopa dosage. The amount of tocapone entering the central nervous system is small, but it has been shown to inhibit central COMT activity in animals. Toxicology research:

Genotoxicity: Tokabene's in vitro mouse lympho / thymidine kinase assay has chromosome aberration effects under metabolically activated conditions. In the Ames test, in vitro V79 / HPRT gene mutation test or off-program DNA synthesis test, tocapone did not show mutagenic effects. No human chromosome aberration was observed in human lymphocytes cultured in vitro or in vivo micronucleus test in mice.

Reproductive toxicity: Tokapeng rats have a dose of 300 mg / kg / d (in mg / m, 5.7 times the human dose), and have no effect on fertility and general reproductive behavior. Tocapone was administered at 300 mg / kg / day and 400 mg / kg / day (in mg / m, respectively, 5.7 and 15 times the recommended daily clinical dose) in pregnant rats and rabbits during organogenesis. Teratogenic effects. However, at 100 mg / kg / day and above, the abortion rate of rabbits increased. Maternal toxicity (loss of weight gain, death) was seen at 300 mg / kg in rats and 400 mg / kg in rabbits. Female rats were given tocapone 250 / 150mg / kg / day at the end of pregnancy and lactation (dose decreased from 250 to 150mg / kg / day at the end of pregnancy due to high maternal mortality). Rats have impaired growth and learning ability. Tocapone is often used clinically in combination with zotodopa / carbidopa, which is known to cause visceral and skeletal deformities in rabbits. Tokapone (100mg / kg / day) and zotodopa / carbidopa (80 / 20mg / kg / day) combined with zotodopa / carbidopa after pregnancy By comparison, the incidence of fetal malformations (mainly external and foot bone defects) increased. At this time, the exposure (in AUC) of tocapone was 0.5 times that expected, and the plasma exposure of zotodopa was 6 times higher than that under treatment conditions. In rat embryo-fetal development studies, tocapone (10, 30, and 50 mg / kg / day) was used in combination with zotodopa / carbidopa (120 / 30mg / kg / day) and zotodopa / Carbidopa was applied alone, and the fetal weight was reduced. At this time, the exposure of tocapone was 0.5 times or higher than that expected, and the exposure of zodopa was 21 times or higher than expected. Tokapen alone was administered at doses up to 50 mg / kg / day (1.4 times the expected human plasma exposure) without a decrease in fetal weight. Animal studies have shown that tocapone can be secreted from the milk of female rats. It is unknown whether tocapone is secreted by human milk. Because many drugs are secreted in human milk, breastfeeding women should be used with caution. Carcinogenicity: Carcinogenicity studies of Tocapone and mice were performed using adulterated method. Mice were administered at doses of 100, 300, and 800 mg / kg / day (equivalent to 0.8, 1.6, and 4 times the recommended daily clinical dose of 600 mg), and the dosing cycle was 80 (female) or 95 (male) weeks. Rats were administered at doses of 50, 250, and 450 mg / kg / day (tokapon exposure in male rats was 1, 6.3, and 13 times that in humans, and 1.7, 11.8, and 26.4 times in female rats). The cycle is 104 weeks. The incidence of uterine adenocarcinoma in female rats increased at an exposure equivalent to 26.4 times that of humans. There is evidence of renal tubular damage and tubular tumor formation in rats. The incidence of renal tubular adenomas in female rats in the middle and high dose groups is low. Renal tubular cell carcinomas have appeared in male rats in the medium and high dose groups and in female rats in the high dose group. The male rats in the high dose group have statistical significance. Increase. When the exposure was 1 (male) or 1.7 (female) times the human exposure, no kidney tumor was seen.

Tocapone pharmacokinetics

The pharmacokinetics of tocapone are linear in the dose range of 50 mg to 400 mg, which does not depend on the combined administration of zotodopa / carbidopa. The clearance half-life of tocapone is 2 to 3 hours without significant drug accumulation. At three doses of 100 mg or 200 mg three times a day, the Cmax was approximately 3 g / ml and 6 g / ml, respectively. Absorption: Tocapone absorbs quickly and its Tmax is about 2 hours. After oral administration, the absolute bioavailability is about 65%. Eating 1 to 2 hours before or after tocapone administration can reduce relative bioavailability by 10% to 20%. Distribution: Tokabon's steady-state distribution volume is small (9L) and is not widely distributed into tissues due to its high plasma protein binding rate. In the concentration range of 0.32 to 210 g / ml, the plasma protein binding rate is> 99.9%. In vitro tests have shown that tocapone binds primarily to serum albumin. Metabolism and clearance: Tocapone is almost completely metabolized before excretion, and only a small amount (0.5% of the used dose) of the prototype is found in the urine.

Tocapone's main metabolic pathway is glucuronidation; it is inactivated by conjugation with glucuronide. In addition, this compound is methylated by catechol-oxy-methyltransferase (COMT) to 3-oxo-methyl-tocapone, which is metabolized to a primary alcohol (methyl hydroxylation) ), And then oxidized to hydroxy acid, in vitro experiments suggest that it may be catalyzed by cytochromes P450 3A4 and P4502S6. Degradation to amines and subsequent N-acetylation occur only to a small extent. After oral administration of 14C-labeled tocapone, 60% of the markers were excreted with urine and 40% were excreted with feces. Tocapone is a drug with a low excretion rate (excretion rate = 0.15%). It has a moderate systemic clearance rate of about 7 L / hour.

Special populations: The pharmacokinetics of tocapone did not differ significantly among different genders, ages, weights, and races.

Renal Impairment: The pharmacokinetics of tocapone have not been specifically investigated in patients with renal impairment, however, the relationship between renal function and pharmacokinetics of tocapone has been investigated using a population pharmacokinetic approach during clinical trials . The data of more than 400 patients have been confirmed to be in a wide range of creatinine clearance (30ml / min to 130ml / min). The pharmacokinetics of tocapone are not affected by renal function. This can be explained by the fact that only negligible and unchanged tocapone (0.5%) is excreted with urine. Tocapone's glucuronic acid conjugate is mainly excreted with urine, but also excreted with bile. The accumulation of this stable, inactive metabolite will not constitute a creatinine clearance above 25ml / min in patients with renal impairment. Threat (see Dosage and Administration). Due to the high protein binding rate of tocapone, tocopherol will not be cleared by hemodialysis.

It is reported in the literature that the results of pharmacokinetics and pharmacodynamics of tocapone in healthy elderly volunteers show that 200 mg of tocapone orally three times a day, Cmax is 6 to 7 mg.L-1, AUC is about It is 24-27mgL-1.h-1; its pharmacokinetics is linearly correlated, and its absorption and elimination are fast, with a terminal half-life of 2 hours. ^[2]