Tolcapone

Tolcapone is an orally active, selective and reversible catechol-O-methyltransferase (COMT) inhibitor. Administered concomitantly with levodopa and an aromatic amino acid decarboxylase inhibitor (AADC-I), it leads to more stable plasma levels of levodopa by reducing metabolism of levodopa to 3-methoxy-4-hydroxy-L-phenylalanine (3-OMD).

High levels of plasma 3-OMD have been associated with poor response to levodopa in Parkinson’s disease patients. Tolcapone markedly reduces the formation of 3-OMD.

Pharmacodynamic effects

Studies in healthy volunteers have shown that tolcapone reversibly inhibits human erythrocyte COMT activity after oral administration. The inhibition is closely related to plasma tolcapone concentration. With 200 mg tolcapone, maximum inhibition of erythrocyte COMT activity is, on average, greater than 80%. During dosing with tolcapone 200 mg three times daily, erythrocyte COMT inhibition at trough is 30% to 45%, with no development of tolerance.

Transient elevation above pretreatment levels of erythrocyte COMT activity was observed after withdrawal of tolcapone. However, a study in Parkinson’s patients confirmed that after treatment discontinuation there was no significant change in levodopa pharmacokinetics or in patient response to levodopa compared to pretreatment levels.

When tolcapone is administered together with levodopa, it increases the relative bioavailability (AUC) of levodopa approximately twofold. This is due to a decrease in clearance in L-dopa resulting in a prolongation of the terminal elimination half-life (t_1/2) of levodopa. In general, the average peak levodopa plasma concentration (C_max) and the time of its occurrence (t_max) were unaffected. The onset of effect occurs after the first administration. Studies in healthy volunteers and parkinsonian patients have confirmed that the maximum effect occurs with 100–200 mg tolcapone. Plasma levels of 3-OMD were markedly and dose-dependently decreased by tolcapone when given with levodopa/AADC-I (aromatic amino acid decarboxylase – inhibitor) (benserazide or carbidopa).

Tolcapone’s effect on levodopa pharmacokinetics is similar with all pharmaceutical formulations of levodopa/benserazide and levodopa/carbidopa; it is independent of levodopa dose, levodopa/AADC-I (benserazide or carbidopa) ratio and the use of sustained-release formulations.

In the therapeutic range, tolcapone pharmacokinetics are linear and independent of levodopa/AADC-I (benserazide or carbidopa) coadministration.

Absorption

Tolcapone is rapidly absorbed with a t_max of approximately 2 hours. The absolute bioavailability of an oral administration is around 65%. Tolcapone does not accumulate with three times daily dosing of 100 or 200 mg. At these doses, C_max is approximately 3 and 6 µg/ml, respectively. Food delays and decreases the absorption of tolcapone, but the relative bioavailability of a dose of tolcapone taken with a meal is still 80% to 90%.

Distribution

The volume of distribution (V_ss) of tolcapone is small (9 l). Tolcapone does not distribute widely into tissues due to its high plasma protein binding (>99.9%). In vitro experiments have shown that tolcapone binds mainly to serum albumin.

Biotransformation/Elimination

Tolcapone is almost completely metabolised prior to excretion, with only a very small amount (0.5% of dose) found unchanged in urine. The main metabolic pathway of tolcapone is conjugation to its inactive glucuronide. In addition, the compound is methylated by COMT to 3-O-methyl-tolcapone and metabolised by cytochromes P450 3A4 and P450 2A6 to a primary alcohol (hydroxylation of the methyl group), which is subsequently oxidised to the carboxylic acid. The reduction to a putative amine, as well as the subsequent N-acetylation, occurs to a minor extent. After oral administration, 60% of drug-related material is excreted into urine and 40% into faeces.

Tolcapone is a low-extraction-ratio drug (extraction ratio = 0.15), with a moderate systemic clearance of about 7 L/h. The t_1/2 of tolcapone is approximately 2 hours.

Hepatic impairment

Because of the risk of liver injury observed during post-marketing use, tolcapone is contraindicated in patients with liver disease or increased liver enzymes. A study in patients with hepatic impairment has shown that moderate non-cirrhotic liver disease had no impact on the pharmacokinetics of tolcapone. However, in patients with moderate cirrhotic liver disease, clearance of unbound tolcapone was reduced by almost 50%. This reduction may increase the average concentration of unbound drug two-fold.

Renal impairment

The pharmacokinetics of tolcapone have not been investigated in patients with renal impairment. 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 (30-130 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 is excreted in the urine, and the main metabolite, tolcapone-glucuronide, is excreted both in urine and in bile (faeces).

Preclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction.

Carcinogenesis, mutagenesis

3% and 5% of rats in the mid- and high- dose groups, respectively, of the 24-month carcinogenicity study were shown to have renal epithelial tumours (adenomas or carcinomas). However, no evidence of renal toxicity was observed in the low-dose group. An increased incidence of uterine adenocarcinomas was seen in the high-dose group of the rat carcinogenicity study. There were no similar renal findings in the mouse or dogs carcinogenicity studies.

Mutagenesis

Tolcapone was shown not to be genotoxic in a complete series of mutagenicity studies.

Toxicity to reproduction

Tolcapone, when administered alone, was shown to be neither teratogenic nor to have any relevant effects on fertility.