Real‐world considerations regarding the use of the combination of levodopa, carbidopa, and entacapone (Stalevo^®) in Parkinson's disease

Abstract

An important aim in long‐term levodopa therapy is to prolong the duration of symptomatic efficacy of each dose without increasing peak plasma concentrations above the threshold for the emergence of dyskinesias.One strategy is to enhance levodopa delivery to the brain by co‐administering it with inhibitors of peripheral dopa decarboxylase and catechol‐O‐methyltransferase (COMT). Levodopa, carbidopa and entacapone (LCE), available in a range of fixed‐dose combinations as the branded formulation Stalevo (Orion Pharma), has been developed to address this requirement and has been in general use for 20 years, having first been evaluated in randomized controlled trials.Experience with LCE has established that improved levodopa pharmacokinetics achieved with dual‐enzyme inhibition are translated into improved clinical efficacy, including the possibility of reducing total levodopa dosage with no loss of therapeutic effect.The ease and tolerability of switching to LCE has been affirmed in the SIMCOM trial and by personal experience detailed in this review.Some 300,000 patient‐years of safety data are available for LCE, including trial data for up to 5 years. Most adverse effects associated with LCE are attributable to the levodopa component rather than the enzyme inhibitors. The hepatotoxicity observed with the class comparator tolcapone has not been observed with entacapone, the COMT inhibitor in LCE, and there is no formal requirement to monitor liver function during LCE therapy. Other common side effects include diarrhoea, which is one of the more prominent non‐dopaminergic adverse events, and urine discolouration, which is harmless but about which patients may require reassurance.

The Catechol O-Methyltransferase Inhibitor Entacapone in the Treatment of Parkinson’s Disease: Personal Reflections on a First-in-Class Drug Development Programme 40 Years On

“…For some time now, entacapone has overwhelmingly been used in the fixed-dose-ratio triple preparation of levodopa-carbidopa-entacapone branded as Stalevo®. This preparation, which presents levodopa in a dose range of 50-200 mg in a 4:1 ratio with carbidopa and a fixed dose of 200 mg of entacapone, is indicated on the basis of randomised controlled trials [30][31][32][33][34][35][36][37][38][39] for patients with idiopathic PD having end-of-dose motor fluctuations not stabilised on levodopa/DDC treatment to (i) substitute for immediate-release carbidopa/levodopa and entacapone previously administered as individual products or (ii) replace immediate-release carbidopa/levodopa therapy (without entacapone) in patients taking a total daily dose of levodopa of up to 800 mg and not experiencing dyskinesias.…”

“…Carbidopa was selected as the DDCI for this purpose owing to its wide availability and use. [39]. Entacapone (alone or in the Stalevo TC) has now been approved and introduced in clinical practice in over 120 countries worldwide.…”

Salidroside Mediated the Nrf2/GPX4 Pathway to Attenuates Ferroptosis in Parkinson’s Disease

“…Pathologically, PD is characterized by neural inclusions such as Lewy bodies and Lewy neurites, cell loss, and a reduction in dopaminergic neurons in the substantia nigra pars compacta, associated with systemic progressive iron accumulation [ 1 ]. Current PD drug therapies aim to enhance dopamine neurotransmission to alleviate symptoms [ 3 ]. The therapeutic arsenal includes dopamine precursors like L-DOPA, dopamine agonists, and dopamine metabolism inhibitors [ 4 ].…”

Bioactive components and mechanisms of Pu-erh tea in improving levodopa metabolism in rats through COMT inhibition

“…For a complete evaluation of its efficacy, more studies are needed on opicapone. [11][12][13] Consequently, the discovery of better COMT inhibitors with improved pharmacokinetic properties, safety profiles, and clinical efficacy is imperative.…”