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Catechol-O-methyl transferase inhibitor.
Pharmacology: Entacapone belongs to a new therapeutic class, catechol-O-methyl transferase (COMT) inhibitors. It is a reversible, specific, and mainly peripherally-acting COMT inhibitor designed for concomitant administration with levodopa preparations. Entacapone decreases the metabolic loss of levodopa to 3-O-methyldopa (3-OMD) by inhibiting the COMT enzyme. This leads to an increase in the bioavailability of levodopa and an increased amount of levodopa available to the brain. These effects have been demonstrated in clinical studies where addition of entacapone to levodopa increased 'ON' time by up to 16% and reduced 'OFF' time by up to 24%.
Entacapone inhibits the COMT enzyme mainly in peripheral tissues. COMT inhibition in red blood cells closely follows the plasma concentrations of entacapone, thus clearly indicating the reversible nature of COMT inhibition.
Pharmacokinetics: Absorption: There are large intra- and interindividual variations in the absorption of entacapone. The peak concentration (Cmax) in plasma is usually reached about 1 hr after a 200-mg entacapone tablet. The drug is subject to extensive first-pass metabolism. The bioavailability of entacapone is about 35% after an oral dose. Food does not affect the absorption of entacapone to any significant extent.
Distribution: After absorption from the gastrointestinal tract, entacapone is rapidly distributed to the peripheral tissues with a distribution volume at steady state of 20 L. Approximately 92% of the dose is eliminated during β-phase with a short elimination half-life of 30 min. The total clearance of entacapone is about 800 mL/min.
Entacapone is extensively bound to plasma proteins, mainly to albumin. In human plasma, the unbound fraction is about 2% in the therapeutic concentration range. At therapeutic concentrations, entacapone does not displace other extensively bound drugs (eg, warfarin, salicylic acid, phenylbutazone or diazepam), nor is it displaced to any significant extent by any of these drugs at therapeutic or higher concentrations.
Metabolism: A small amount of entacapone, the (E)-isomer is converted to its (Z)-isomer. The (E)-isomer accounts for 95% of the AUC of entacapone. The (Z)-isomer and traces of other metabolites account for the remaining 5%.
Elimination: The elimination of entacapone occurs mainly by nonrenal metabolic routes. It is estimated that 80-90% of the dose is excreted in faeces, although this has not been confirmed in man. Approximately 10-20% is excreted in urine. Only traces of entacapone are found unchanged in urine. The major part (95%) of the product excreted in urine is conjugated with glucuronic acid. Of the metabolites found in urine only about 1% have been formed through oxidation.
Characteristics in Patients: The pharmacokinetic properties of entacapone are similar in both young and elderly adults. The metabolism of Comtan is slowed in patients with mild to moderate liver insufficiency (Child-Pugh Class A and B), which leads to an increased plasma concentration of entacapone both in the absorption and elimination phases (see Contraindications). Renal impairment does not affect the pharmacokinetics of entacapone. However, a longer dosing interval may be considered for patients who are receiving dialysis therapy.
Toxicology: Preclinical Safety Data: Preclinical data revealed no special hazard for humans based on conventional studies of safety, pharmacology, repeated dose toxicity, genotoxicity, and carcinogenic potential. In repeated dose toxicity studies, anaemia most likely due to iron-chelating properties of entacapone was observed. In studies of reproduction toxicity, decreased foetal weight and a slightly delayed bone development were noticed in rabbits at systemic exposure levels in the therapeutic range.
