Source: European Medicines Agency (EU) Revision Year: 2018 Publisher: Novartis Europharm Limited, Vista Building, Elm Park, Merrion Road, Dublin 4, Ireland
Pharmacotherapeutic group: other dopaminergic agents
ATC code: N04BX02
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.
In two phase III double-blind studies in a total of 376 patients with Parkinson’s disease and end-of- dose motor fluctuations, entacapone or placebo was given with each levodopa/dopa decarboxylase inhibitor dose. The results are given in Table 2. In study I, daily ON time (hours) was measured from home diaries and in study II, the proportion of daily ON time.
Table 2. Daily ON time (Mean ± SD):
| Study I: Daily On time (h) | |||
|---|---|---|---|
| Entacapone (n=85) | Placebo (n=86) | Difference | |
| Baseline | 9,3±2,2 | 9,2±2,5 | |
| Week 8-24 | 10,7±2,2 | 9,4±2,6 | 1h 20 min (8,3%) CI 95% 45min, 1h 56 min |
| Study II: Proportion of daily On time (%) | |||
| Entacapone (n=103) | Placebo (n=102) | Difference | |
| Baseline | 60,0±15,2 | 60,8±14,0 | |
| Week 8-24 | 66,8±14,5 | 62,8±16,80 | 4,5% (0h 35min) CI 95% 0,93%, 7,97% |
There were corresponding decreases in OFF time.
The % change from baseline in OFF time was –24% in the entacapone group and 0% in the placebo group in study I. The corresponding figures in study II were –18% and –5%.
There are large intra- and interindividual variations in the absorption of entacapone.
The peak concentration (Cmax) 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.
After absorption from the gastrointestinal tract, entacapone is rapidly distributed to the peripheral tissues with a distribution volume of 20 litres at steady state (Vdss). 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.
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) (see section 4.5).
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.
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 (see section 4.3). 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.
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