Tolcapone, a potent selective reversible COMT inhibitor, was launched in Europe in 1997, and in the US in 1998 (Leegwater-Kim and Waters 2006
). Its efficacy as adjunct to levodopa therapy is attributed to the peripheral COMT inhibition, whereas there is still some debate around clinical relevance associated to the central activity. Results of clinical trials conducted in PD patients, confirm that tid administration of tolcapone magnifies levodopa motor benefit. Improvement had already been observed with a single 200 mg dose (Napolitano et al 1999
Compared with levodopa/DDCI alone, single or multiple doses of tolcapone 100 or 200 mg increased levodopa bioavailability by 1.3 to 2.1 fold, both in healthy volunteers and in PD patients (Limousin et al 1995
Pharmacological profile of tolcapone is characterized by a greater bioavailability, and so has a greater area under the curve, Tmax
and COMT enzyme affinity, compared with entacapone. Tolcapone increases the levodopa half-life by 80% versus 40% for entacapone, the levodopa area under the curve by 80% versus 40% for entacapone, providing a greater decrease in the formation of O-methyl-dopa as well (Factor et al 2001
The results of a long-term comparative study between tolcapone and entacapone, suggest that tolcapone is more effective, and this difference in response would be predicted by the pharmacological differences between the two agents (Onofrj et al 2001
). The study, performed in patients with fluctuating PD, compared efficacy and tolerability of tolcapone and entacapone, evaluating the effects prospectively at 6, 12, 24, and 36 months. Fourteen patients were enrolled under tolcapone treatment, and eleven patients were enrolled under entacapone treatment. Tolcapone showed more effectiveness in lowering UPDRS motor score and complication subscores, duration of “off” periods, and levodopa doses requirement (UPDRS motor score change was −5.07 ± 1.48 in tolcapone group, and +2.46 ± 2.76 for entacapone (p < 0.02); duration of “off” period was −1 ± 0.23 for tolcapone, 0 ± 0.27 for entacapone (p < 0.03), lowering of L–DOPA dose was −400 ± 70.7 for tolcapone and +179.2 ± 160.8 for entacapone (p < 0.04).
Another study in 40 patients with severe PD, with open design and direct switch-over from tolcapone to entacapone, was prompted because of mandatory indications of the European drugs authority, who withdrew tolcapone from market in November 1998. “On” time was increased by 15% during tolcapone treatment (p < 0.05), and by 8% during entacapone treatment, whereas “off” time was decreased by 16% during tolcapone and by 7% during entacapone treatment. The reduction of L-DOPA was significantly improved by tolcapone compared with entacapone (p = 0.05) (Lees et al 2007
). IGA (Investigator Global Assessment) for wearing off severity, indicated that 70–73% of the patients receiving tolcapone, and 56% of patients receiving entacapone, had a relevant improvement (p = 0.01).
A recent double blind study assessed patients receiving entacapone after random assignement to continue entacapone (n = 75) or switch to tolcapone (n = 75). The “on” time increased by ≥1 hour day in 43% of entacapone patients and in 53% of tolcapone patients and by ≥3 hours day in 13% and 25% of patients, respectively. The IGA indicated moderate/marked improvement in 25% of entacapone patients and 39% receiving tolcapone. No differences were observed in the rate of dyskinesias and adverse events leading to discontinuation of treatment (Pahwa et al 2006
Safety and tolerability were evaluated with a focus on liver transaminase elevations and hepatotoxicity; 677 levodopa-naïve patients were randomized to receive placebo or tolcapone as add-on therapy to standard doses of levodopa (The Entacapone to Tolcapone Switch Study Investigators 2007
). Liver transaminase elevations above the upper normal limit (ULN) occurred in 20.2% and 27.5% of patients in the placebo and tolcapone groups, respectively. Elevations of ULN ≥3 fold occurred in 1.2% and 1.8% of placebo and tolcapone patients, respectively. No serious hepatotoxicity events were reported.
Efficacy of oral tolcapone as adjunct therapy to levodopa/DDCI, was demonstrated in several trials, although only in the short period (3 weeks’ to 3 months’ duration), both in fluctuating and stable PD patients (Suchowersky et al 2001
Clinical trials conducted in PD patients with motor fluctuations (wearing off, predictable “on-off”), were analyzed by a Committee of the American Academy of Neurology. The Committee recognized tolcapone is useful in reducing the “off” time, the need of levodopa daily dose, and prolonging the “on” phase.
Recently, also data from a comparator study (the SWITCH study) were presented. The aim of the study was to determine if switching from entacapone to tolcapone improves motor features. In the per-protocol analysis, a statistically significant greater proportion of patients switched to tolcapone, had at least 3 hours/day of additional “on” time (p = 0.018). More patients on tolcapone were judged to have a moderate or marked improvement in the IGA, although not statistically significant. Also the number of responders was higher on tolcapone, which appeared to have greater long-term benefits compared to entacapone ().
Efficacy of oral tolcapone 100 mg, entacapone, and rasagiline evaluated in terms of increasing hours of “on” time, decreasing hours of “off” time, and levodopa requirement
In patients with stable disease, tolcapone determines improvement from baseline in various end-points in a short-term study (Suchowersky et al 2001
), showing an overall global improvement in 77% of patients at the IGA score, after 4 weeks double-blind treatment.
These preliminary results suggest potential benefit on both motor and non-motor fluctuations. In this respect, patient-perceived benefit, obtained by smoother levodopa response, might be regarded also as an indirect effect of improved non-motor fluctuations.
With regard to safety, dopaminergic-related adverse events were the most frequently reported in patients receiving 200 mg tolcapone tid. Such events (nausea, vomiting, dyskinesia, orthostatic complaints, sleep disorders, dystonia, confusion, hallucination), are likely a consequence of the increase in levodopa concentrations, especially at the beginning of treatment, and are mostly resolved with a reduction in levodopa dose. New or worsening dyskinesias were one of the most commonly reported dopaminergic-related adverse events (25%–62% with tolcapone, 100 mg 3 times daily, 31%–66% with 200 mg 3 times daily); in any case they were not a reason for withdrawal (Deane et al 2004
). Some major concerns have been raised in the past over the emergence of liver toxicity (Watkins 2000
For this reason, marketing authorization for tolcapone was suspended in the EU (late 1998), and labeling was tightened in the US. However, suspension of the marketing authorization in the EU was later lifted following EMEA recommendation (EMEA 2004
The cause of hepatotoxicity has not been clearly established yet, although the current hypothesis suggests a possible interference with mithocondrial respiration in hepathocytes, by uncoupling oxidative phosphorilation (Borges 2005
Three cases of fatal fulminant hepatic failure were reported with tolcapone in 1998, but it should be noted that liver function had not been properly monitored in these patients and that the liver dysfunction emerged 2–6 months after starting treatment (Olanow 2000
). A recent review of tolcapone global safety (Valeant Pharmaceuticals International data on file), reported severe hepatocellular injury only in 0.04% of patients over the last 7 years, whereas the majority of patients experiencing liver toxicity, only showed an elevations in liver transaminases without clinical signs or symptoms.
In a review of clinical data on 1535 patients (Olanow 2000
), the expert panel also noted that about half the patients who continued tolcapone therapy experienced a normalization of ALT/AST levels within 1–3 months, whereas patients who discontinued tolcapone experienced the normalization after just 2–3 weeks. These data are crucial in the evaluation of tolcapone’s role in PD therapy; in fact, due to its fast onset of action, the identifications of responders can occur early, when the liver damage is probably still in a reversible initial phase, so non-responders may easily withdraw before liver damage is established, whereas responders should be strictly monitored, especially in the first 6 months.
In summary, tolcapone is a useful option for patients with idiopathic, fluctuating PD patients (Colosimo 1999
). Clinical practice suggests that tolcapone is more effective than entacapone and it can be successfully associated to levodopa preparations. In addition it has central activity with potential benefits on mood and cognition although this might be observed only at doses of 200 mg tid. Data on tolcapone effect in patients who have not benefited from entacapone (this would be the target population according to EMEA guidelines) are still lacking. Randomized trials are warranted to demonstrate that adding tolcapone in these individuals is indeed beneficial.