Entacapone

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 a higher levodopa AUC. The amount of levodopa available to the brain is increased. Entacapone thus prolongs the clinical response to levodopa.

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.

General characteristics of the active substance

Absorption

There are large intra- and interindividual variations in the absorption of entacapone.

The peak concentration (C_max) in plasma is usually reached about one hour after ingestion of a 200 mg entacapone tablet. The substance 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 of 20 litres at steady state (Vd_ss). Approximately 92% of the dose is eliminated during ß-phase with a short elimination half-life of 30 minutes. 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 2.0% in the therapeutic concentration range. At therapeutic concentrations, entacapone does not displace other extensively bound substances (e.g. warfarin, salicylic acid, phenylbutazone, or diazepam), nor is it displaced to any significant extent by any of these substances at therapeutic or higher concentrations.

Biotransformation

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%.

Data from in vitro studies using human liver microsomal preparations indicate that entacapone inhibits cytochrome P450 2C9 (IC₅₀ ~4 μM). Entacapone showed little or no inhibition of other types of P450 isoenzymes (CYP1A2, CYP2A6, CYP2D6, CYP2E1, CYP3A and CYP2C19).

Elimination

The elimination of entacapone occurs mainly by non-renal 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 people and older people. The metabolism of the medicinal product 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 in both the absorption and elimination phases. Renal impairment does not affect the pharmacokinetics of entacapone. However, a longer dosing interval may be considered for patients who are receiving dialysis therapy.

Non-clinical data reveal 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. Regarding reproduction toxicity, decreased foetal weight and a slightly delayed bone development were noticed in rabbits at systemic exposure levels in the therapeutic range.