Entacapone

Abstract

Entacapone is a potent and specific peripheral catechol-O-methyltransferase (COMT) inhibitor. It has been shown to improve the clinical benefits of levodopa plus an aromatic L-amino acid decarboxylase inhibitor (AADC) when given to patients with Parkinson’s disease and end-of-dose deterioration in the response to levodopa (the ‘wearing off’ phenomenon). The efficacy of entacapone is currently being assessed in patients with stable Parkinson’s disease. In 2 well conducted trials of 6 months’ duration and smaller short term studies, treatment with entacapone (200mg with each dose of levodopa/AADC inhibitor) was associated with significant increases in daily ‘on’ time and decreases in ‘off’ time. Changes in Unified Parkinson’s Disease Rating Scale (UPDRS) scores concurred with changes in ‘on’ and ‘off’ times: entacapone improved total, activities of daily living and motor function scores, but it had no effect on mentation scores. Entacapone also provided benefits when given with controlled release levodopa/ AADC inhibitor or with standard levodopa/AADC inhibitor and selegiline in small trials. Dopaminergic events, including dyskinesia and nausea, are among the most common events with entacapone, and are related to the drug’s ability to potentiate the effects of levodopa. Diarrhoea, abdominal pain, constipation and urine discolouration are the most common nondopaminergic events, although the latter event is the only one to occur consistently more frequently with entacapone than with placebo. However, adverse events of any type infrequently led to study discontinuation. Conclusions: The efficacy and tolerability of entacapone administered with levodopa/AADC inhibitor have not yet been compared with those of other strategies for the treatment of Parkinson’s disease. However, once the decision to initiate levodopa therapy has been made, studies generally support the use of entacapone as an adjunct to levodopa in patients with Parkinson’s disease and the ‘wearing off’ phenomenon. Results of in vitro and ex vivo studies indicate that entacapone is a potent, specific, reversible and peripherally acting soluble catechol-O-methyltransferase (COMT) inhibitor. The drug has activity against COMT at a number of peripheral sites, but does not alter cerebral COMT activity in vivo at doses used clinically. Entacapone does not affect other enzymes that metabolise catecholamines. Inhibition of COMT activity reduces peripheral degradation of levodopa and increases central levodopa, and therefore dopamine, concentrations. In positron emission tomography studies using fluorodopa (an analogue of levodopa), single doses of entacapone have significantly increased unmetabolised fluorodopa fractions in both patients with Parkinson’s disease and in healthy volunteers. Coadministration of entacapone with levodopa plus an aromatic L-amino acid decarboxylase inhibitor (AADC) potentiates the effects of levodopa in patients with Parkinson’s disease and reduces the ‘wearing off’ phenomenon (see Therapeutic Efficacy and Tolerability summaries). Potentiation of the effects of levodopa by entacapone has also been shown in animals. Therapeutic doses of entacapone have only small effects on epinephrine (adrenaline) and norepinephrine (noradrenaline) levels at rest or during exercise in healthy volunteers or patients with Parkinson’s disease; both catecholamines are primarily metabolically inactivated by COMT and monoamine oxidase (MAO). However, the pattern of metabolism of these agents is altered: plasma 3,4-dihydroxyphenylglycol and 3,4-dihydroxyphenylacetic acid levels are increased and plasma 3-methoxy-4-hydroxyphenylglycol levels are decreased. Compared with either monotherapy, when entacapone and the MAO-A inhibitor moclobemide are coadministered, similar or smaller changes in levels of the catecholamines and their metabolites are observed. Few haemodynamic changes are reported after administration of entacapone to healthy volunteers or patients with Parkinson’s disease. Entacapone is rapidly absorbed after oral administration of a single dose, and mean maximum plasma concentration (C_max) of 1160 to 1500 μg/L are generally reached 0.7 to 1.3 hours after administration of a 200mg dose in patients with Parkinson’s disease. Importantly, no accumulation of plasma entacapone was detected in healthy male volunteers who received 8 daily doses of entacapone 200mg for 5 days. The elimination of entacapone is mainly described by 2 phases; the β-phase represents approximately 90% of elimination and the γ-phase about 10%. The β-phase elimination half-life (t½β) of entacapone after IV administration is 0.5 to 0.7 hours and the y-phase half-life (t½γ) is 2.4 to 3.5 hours. Additional data indicate that the t½ of oral entacapone 200mg is 1 to 2 hours, which is similar to the t½ of levodopa (≈1.7 hours). The mean oral bioavailability of entacapone 200mg was 36% in healthy volunteers. The Z-isomer of entacapone is the main metabolite of entacapone (itself the E-isomer) in human plasma. The area under the plasma concentration-time curve (AUC) of the Z-isomer is approximately 5% of the total AUC of both isomers. About 10% of an oral entacapone dose is excreted into the urine within 8 hours. Entacapone is primarily eliminated via biliary excretion in humans. Impairment of liver function (alcoholic cirrhosis) significantly increases the bioavailability of entacapone 200mg. The pharmacokinetic parameters of single doses of entacapone are not affected in patients with renal failure or in the elderly. Single doses of entacapone 50 to 200mg and repeated entacapone doses (for 7 days to 8 weeks) dose dependently increase the AUC and elimination half-life (t½) of...