Entacapone Increases Levodopa Exposure and Reduces Plasma Levodopa Variability When Used With Sinemet CR

Abstract

Entacapone is a catechol-O-methyltransferase (COMT) inhibitor used as an adjunct to levodopa/dopa decarboxylase inhibitors in the treatment of Parkinson's disease. Entacapone increases the bioavailability and reduces the daily variation of plasma levodopa when administered with standard levodopa preparations. These parameters were studied when entacapone was administered with a controlled-release levodopa preparation after repeated administrations throughout the day in 16 healthy male volunteers. On 2 test days, 200 mg entacapone or placebo was administered 4 times during the day at 4-hour intervals concomitantly with a single dose of controlled-release levodopa/carbidopa 100 mg/25 mg (Sinemet CR). Plasma levodopa, 3-O-methyldopa (3-OMD), and carbidopa concentrations were measured before intake of the medication and then every 30 minutes for 16 hours (until midnight), and less frequently up to 24 hours after the first levodopa dose. The minimum, maximum, and average concentration of levodopa; the daily variation of levodopa concentration; and the area under the time concentration curve (AUC) were calculated. The mean (+/-SD) plasma levodopa AUC was 39% (P = 0.0001) higher with entacapone (11,802 +/- 1454 ng/hour/mL) compared with placebo (8465 +/- 927 ng/hour/mL). The daily variation of plasma levodopa was reduced by about 25% with entacapone (P < 0.01). Entacapone significantly reduced plasma 3-OMD concentration by about 50% (P = 0.0001), indicating marked COMT inhibiting activity. There were no differences in plasma carbidopa concentrations. Entacapone significantly increased the bioavailability of levodopa and reduced its daily variation when administered concomitantly with a controlled-release levodopa preparation.

Comparison of pharmacokinetic profile of levodopa throughout the day between levodopa/carbidopa/entacapone and levodopa/carbidopa when administered four or five times daily

“…This agrees with earlier studies conducted in healthy subjects [2] and patients with PD [5], which have shown that a single administration of LC and entacapone does not increase the C max of levodopa. With different dosing regimens, similar kinds of results (regarding t 1/2 , C min , C max , and AUC of levodopa) have been reported with repeated dosing of entacapone administered together with standard release levodopa/carbidopa [4][5] or with controlled-release levodopa/carbidopa [18]. It has also been reported that co-administration of tolcapone t.i.d.…”

“…The sample-size calculation was based on a previous study with four daily doses of controlled-release LC 100/25 mg and entacapone 200 mg given at 4-h intervals [18]. The sample size needed to produce a statistical power of 80% in this study was nine subjects (with a significance level of 5%).…”

The scientific and clinical basis for the treatment of Parkinson disease (2009)

“…Single doses do not cause a rise in either the maximal plasma concentration (C max ) or the time to reach maximal plasma concentration (T max ), 393,394 but chronic dosing is associated with accumulation over the course of the day. COMT inhibitors are effective when administered in conjunction with either regular or sustained-release Sinemet 395 and increase interdose, trough, and mean levodopa concentrations. 396 Thus, administration of levodopa plus a COMT inhibitor results in smoother plasma levodopa levels and more continuous brain availability compared with levodopa alone.…”

Efficacy and Safety of Adjuvant Treatment with Entacapone in Advanced Parkinson’s Disease with Motor Fluctuation: A Systematic Meta-Analysis

“…Parkinson's disease (PD) is a chronic, progressive neurodegenerative disease with neuropathological hallmarks of the loss of dopaminergic neurons in the Sub-DOI: 10.1159/000479555 stantia Nigra pars compact and the reduction of dopamine in striatum. The clinical features of PD are akinesia, bradykinesia, rigidity and tremors, which are known to be directly related to dopaminergic striatal loss [1].…”