Tolcapone dosing

Clinical studies, available only for entacapone and tolcapone, support preclinical findings. A dose-dependent (100-800 mg) inhibition of the COMT activity of the erythrocytes can be seen after nitrocatechols. However, effective and sufficient dose levels of both entacapone and tolcapone, given concomitantly with L-dopa and DDC inhibitors to patients with Parkinson s disease, appear to be 100-200 mg. However, the treatment strategies of entacapone and tolcapone differ entacapone is a short-acting compound that is given with each dose of L-dopa, and COMT activity may even... 

Tolcapone (Tasmar ) Peripherally blocks COMT metabolism of DA some central activity Start with 1 00 mg with first Sinemet dose once daily if symptoms continue, increase to 2 and then 3 times daily, then to 200 mg each dose usual MD is 1 00 three times daily to minimize risk of side-effects... 

The starting and recommended dose of tolcapone is 100 mg three times daily as an adjunct to carbidopa/L-dopa. Its use is limited by the potential for fatal liver toxicity. Strict monitoring of liver function is required, and tolcapone should be discontinued if liver function tests are above the upper limit of normal or any signs or symptoms suggestive of hepatic failure exist. It should be reserved for patients with fluctuations that have not responded to other therapies. 

Because entacapone has a shorter half-life, 200 mg is given with each dose of carbidopa/L-dopa up to eight times a day. Dopaminergic adverse effects may occur and are managed easily by reducing the carbidopa/L-dopa dose. Brownish-orange urine discoloration may occur (as with tolcapone), but there is no evidence of hepatotoxicity from entacapone. 

For many of the drugs associated with hepatotoxicity, there are examples of structurally related drugs which are latent to bioactivation and toxicity because of the absence of the toxicophore or the existence of alternate metabolic pathways. For example, the hepatotoxicity associated with the use of the anti-Parkinson s agent tolcapone does not occur with the structurally related drug entacapone, despite administration at doses similar to tolcapone (200-1000 mg QD). This disparity may be explained in part by the observation that entacapone does not succumb to the bioactivation reactions of tolcapone in humans (Scheme 15.3) [35]. It is also noteworthy that tolcapone but not entacapone is a potent uncoupler of oxidative... 

Geriatric Considerations - Summary Entacapone inhibits peripheral COMT and increases levodopa s effects. Itsprimary role is as adjunctive therapy to prolong the beneficial effects of levodopa and to decrease end-of-dose fluctuations in response to treatment. Concurrent use of levodopa is necessary for entacapone to be effective and unlike tolcapone, hepatic monitoring is not required. 

Adjunctive treatment of Parkinson s disease PO Initially, 100-200 mg 3 times a day concomitantly with each dose of carbidopa and levodopa. Maximum 600 mg/day Dosage in hepatic impairment Patients with moderate to severe cirrhosis should not receive more than 200 mg tolcapone 3 times a day... 

ALT/AST at baseline then q2 wk for first yr of therapy, q4 wk for next 6 mo, then q8 wk thereafter repeat this cycle if dose increased to 200 mg tid discontinue tolcapone if ALT or AST exceeds upper limit of normal or if clinical signs and symptoms suggest onset of hepatic failure... 

The pharmacologic effects of tolcapone and entacapone are similar, and both are rapidly absorbed, bound to plasma proteins, and metabolized before excretion. However, tolcapone has both central and peripheral effects, whereas the effect of entacapone is peripheral. The half-life of both drugs is approximately 2 hours, but tolcapone is slightly more potent and has a longer duration of action. Tolcapone is taken in a standard dosage of 100 mg three times daily some patients require a daily dose of twice that amount. By contrast, entacapone (200 mg) needs to be taken with each dose of levodopa, up to five times daily. 

Adverse effects of the COMT inhibitors relate in part to increased levodopa exposure and include dyskinesias, nausea, and confusion. It is often necessary to lower the daily dose of levodopa by about 30% in the first 48 hours to avoid or reverse such complications. Other adverse effects include diarrhea, abdominal pain, orthostatic hypotension, sleep disturbances, and an orange discoloration of the urine. Tolcapone may cause an increase in liver enzyme levels and has been associated... 

Entacapone and tolcapone are peripheral inhibitors of catechol-O-methyl-transferase (COMT). COMT metabolises levodopa to an inactive product so their use enables greater amounts of levodopa to reach the brain. They are licensed for use as an adjunct to co-beneldopa and co-careldopa for patients who experience end-of-dose deterioration and cannot be stabilised on the combined preparations alone. 

DOPAMINERGICS - ENTACAPONE, TOLCAPONE DOPAMINERGICS -SELEGIUNE Possible risk of severe hypertensive reactions Theoretical risk due to additive inhibitory effect on dopamine metabolism Manufacturers recommend limiting the dose of selegiline to a maximum of 10 mg... 

Jorga, K. Fotteler, B. Banken, L. Snell, P. Steimer, J.L. Population pharmacokinetics of tolcapone in parkinsonian patients in dose finding studies. Br. J. Clin. Pharmacol. 

Finally, MAO-B inhibitors such as selegiline and the COMT inhibitors tolcapone (Tasmar, Roche) and entacapone (Comtan, Novartis) extend the action of L-dopa. Entacapone is now available in fixed-dose combinations with carbidopa/L-dopa as well (Stalevo, Novartis). 

Muscarinic receptor blockers may improve muscle rigidity and tremor in Parkinsons disease but result in very little improvement in bradykinesia thus, they are mainly considered as adjunctive to the use of drugs that improve dopaminergic function. Selegiline is the inhibitor of MAO type B, and pramipexole is a non-ergot DA receptor agonist. Carbidopa inhibits peripheral AAAD (dopa decarboxylase) tolcapone is an inhibitor of COMT. Levodopa causes a high incidence of dose-dependent dyskinesias that are not slow in onset, like tardive dyskinesia that results from chronic administration of DA receptor blockers. 

FIGURE 20-7 Pharmacological preservation of L-DOPA and striatal dopamine. The principal site of action of inhibitors of catechol-O-methyltransferase (COMT) (such as tolcapone and entacapone) is in the peripheral circulation. They block the O-methylation of levodopa (l-DOPA) and increase the fraction of the drug available for delivery to the brain. Tolcapone also has effects in the CNS. Inhibitors of MAO-B, such as low-dose selegiline and rasagiline, will act within the CNS to reduce oxidative deamination of DA, thereby enhancing vesicular stores. AAD, aromatic L-amino acid decarboxylase DA, dopamine DOPAC, 3,4-dihydroxyphenylacetic acid MAO, monoamine oxidase 3MT, 3-methoxyl-tyramine 3-O-MD, 3-O-methyl DOPA. 

Two COMT inhibitors are available for this use, tolcapone (tasmar) and entacapone (comtan). Tolcapone has a relatively long duration of action, allowing for administration two to three times a day, and appears to act by both central and peripheral inhibition of COMT. The duration of action of entacapone is short, around 2 hours, so it usually is administered simultaneously with each dose of levodopa/carbidopa. The action of entacapone is attributable principally to peripheral inhibition of COMT. The common adverse effects of these agents are similar to those observed in patients treated with levodopa/carbidopa alone and include nausea, orthostatic hypotension, vivid dreams, confusion, and hallucinations. An adverse effect associated with tolcapone is hepatotoxicity tolcapone should be used only in patients who have not responded to other therapies and with appropriate monitoring of hepatic transaminases. Entacapone has not been associated with hepatotoxicity and requires no special monitoring. Entacapone also is available in fixed-dose combinations with levodopa/carbidopa (stalevo). 

Table 3 lists the dose and incidence of the hepatotoxicity for various drugs, some of which have been withdrawn as a result of these findings. Some of the drugs show effects on liver function earlier than the actual onset of liver toxicity, with serum aminotransferase levels raised by threefold the upper limit of normal (ULN). The incidence of this is much higher and can show a classical dose response for instance, tolcapone, a catechol-O-methyltransferase inhibitor used as an adjunct to levodopa in Parkinson s disease, produces threefold the ULN in 1-3% of patients receiving 100 mg TID and 3.7% of patients receiving 200 mg TID (Olanow and Watkins 2007). Tolcapone, an o-nitrocatechol, is metabohzed to reactive intermediates - o-quinone or quinoneimine species - by human fiver microsomes (Smith et al. 2003). 

Entacapone had no effect on the pharmacokinetics or efficacy of apomorphine in a single-dose study. Similarly, tolcapone had no relevant effect on single-dose apomorphine. 

The evidence from these single-dose studies suggest that there is no pharmacokinetic interaction between entacapone or tolcapone and apomorphine, and that the drugs can be used together without alteration of the apomorphine dose. However, fiirther data are required from longer-term concurrent use to confirm this. Until more is known, increased monitoring during concurrent use of COMT inhibitors and apomorphine may be prudent, as is recommended by the manufacturers. ... 

Ondo WG, Hunter C, Vucng KD, Jankovic VI The pharmacddnetic and clinical effects of tolcapone on a sii e dose of apcmux ii iine in Parkinson s disease. Parldnsonism Relat Disord (2000) 6,237-40. 

In a single dose study, there was no adverse effect on heart rate or blood pressure when entacapone was given with moclobemide (a RIMA), but caution is recommended until further clinical experience is gained. The COMT inhibitors may be used with the MAO-B inhibitors (such as selegiline). However, the manufacturers of entacapone and tolcapone contraindicate concurrent use of non-selective MAOIs or a combination of both a RIMA and a MAO-B inhibitor. 

Entacapone and imipramine did not interact adversely in a single-dose study. Similarly, tolcapone and desipramine did not interact adversely. Nevertheless, the manufacturers of entacapone and tolcapone recommend caution if they are used with tricyclic antidepressants or other drugs that inhibit noradrenaline (norepinephrine) uptake, such as maprotiline or venlafaxine. 

Entacapone and tolcapone increase the AUC of levodopa given with benserazide or carbidopa. This may require a reduction in the levodopa dose to avoid symptoms of dopamine excess when first starting the COMT inhibitor. Tolcapone increases the levels of benserazide, but neither entacapone nor tolcapone alters carbidopa pharmacokinetics. 

The effects of COMT inhibitors on the pharmacokinetics of dopa-decar-boxylase inhibitors has also been studied. Neither entacapone nor tolcapone altered the pharmacokinetics of carbidopa. However, tolcapone increased the serum levels of benserazide in patients with Parkinson s disease. The benserazide levels remained within the usual range in patients taking levodopa products containing benserazide 25 mg and tolcapone 200 mg three times daily. However, with a 50-mg dose of benserazide the AUC of benserazide was increased 4.8-fold with standard-release preparation and 2.3-fold with a controlled-release preparation. ... 

Dingemanse J, JorM K, Ziircher G, Schmitt M, Seidek G, da Prada M, van Brummelen P. Phamacokinetic-pharmacodynamic interaction between the COMT inhibitor tolcapone and single-dose levodopa. BrJ Clin Pharmacol ( 995) 40,253-62. 

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