Effects of One-Day Application of Levodopa/Carbidopa/Entacapone versus Levodopa/Carbidopa/Opicapone in Parkinson's Disease Patients

Abstract

The catechol-O-methyltransferase inhibitors entacapone and opicapone prolong the efficacy of conventional oral levodopa/dopa decarboxylase inhibitor formulations through an increase in levodopa plasma bioavailability. Catechol-O-methyltransferase inhibitors influence the homocysteine metabolism associated with levodopa/dopa decarboxylase application. The objectives of this study were to compare the impact of additional single-day entacapone or opicapone intake on the pharmacokinetic plasma behaviour of levodopa, 3-O-methyldopa and total homocysteine in 15 Parkinson's disease patients, with concomitant scoring of motor symptoms, under standardized conditions. The patients received opicapone plus two doses of 100 mg levodopa/carbidopa and, one week later, two doses of levodopa/carbidopa/entacapone or vice versa. Levodopa, 3-O-methyldopa and total homocysteine were determined with reversed-phase high-performance liquid chromatography. Levodopa bioavailability and its maximum concentration were higher with opicapone. The computed peak-to-trough difference was lower after the second levodopa administration with entacapone. The fluctuation index of levodopa did not differ between both conditions. 3-O-methyldopa decreased on both days. Homocysteine levels did not significantly vary between both conditions. A significant homocysteine decrease occurred with entacapone, but not with opicapone. Motor behaviour improved with entacapone, but not with opicapone. Opicapone baseline scores were significantly better, and thus the potential for the improvement in motor symptoms was lower compared with the entacapone condition. The higher levodopa bioavailability with opicapone suggests that it is more efficacious than entacapone for the amelioration of "off" phenomena in fluctuating patients when co-administered with a levodopa/dopa decarboxylase inhibitor regimen. Both compounds prevented an increase in homocysteine, which is a metabolic marker for an impaired capacity in the performance of methylation processes.

Keywords: 3-O-methyldopa; Parkinson’s disease; entacapone; homocysteine; levodopa; opicapone.

Figure 1

Curve of L-dopa plasma concentrations. All data are given as mean ± standard error of means (SEM); min, minutes; ↑ marks the L-dopa/DDI intake at moment 0 and after 240 min; opicapone was taken at −30 min; L-dopa plasma levels are given in ng/mL, thcys concentrations in µmol/L; lines of the L-dopa/carbidopa plus opicapone condition are dashed with ■; lines of the L-dopa/carbidopa/entacapone condition are continuous with ▲; comparisons of the post hoc analysis: *, p < 0.05, ** p < 0.01, *** p < 0.001; * reports comparisons against moment 0; #, p < 0.05, ## p < 0.01, ### p < 0.001; # reports comparisons against moment 30; $, p < 0.05; $ reports comparisons against moment 60; + p < 0.05, + reports comparisons against moment 120; &, p < 0.05; & reports comparisons against moment 180; “, p < 0.05; “““, p < 0.001; “ reports comparisons against moment 240; o, p < 0.05; ooo, p < 0.001; o reports comparisons against moment 300; symbols for the post hoc analysis and error bars are above the curve of the L-dopa/carbidopa plus opicapone condition; symbols for the post hoc analysis and error bars are below the curve of the L-dopa/carbidopa/entacapone condition.

Figure 2

Curve of 3-OMD levels. All data are given as mean ± standard error of means (SEM); min, minutes; opicapone was taken at −30 min; L-dopa and 3-OMD plasma levels are given in ng/mL, thcys concentrations in µmol/L; lines of the L-dopa/carbidopa plus opicapone condition are dashed with ■; lines of the L-dopa/carbidopa/entacapone condition are continuous with ▲; error bars are above the curve of the L-dopa/carbidopa plus opicapone condition; error bars are below the curve of the L-dopa/carbidopa/entacapone condition.

Figure 3

Curve of total homocysteine. All data are given as mean ± standard error of means (SEM); min, minutes; opicapone was taken at −30 min; thcys concentrations in µmol/L; lines of the L-dopa/carbidopa plus opicapone condition are dashed with ■; lines of the L-dopa/carbidopa/entacapone condition are continuous with ▲; error bars are above the curve of the L-dopa/carbidopa plus opicapone condition; error bars are below the curve of the L-dopa/carbidopa/entacapone condition.

Figure 4

Scoring outcomes over the interval. All data are given as mean ± standard error of means (SEM); min, minutes; UPDRS III, Unified Parkinson’s Disease Rating Scale for motor examination; lines of the L-dopa/carbidopa plus opicapone condition are dashed with ■; lines of the L-dopa/carbidopa/entacapone condition are continuous with ▲; comparisons of the post hoc analysis: * p < 0.05, ** p < 0.01; * reports comparisons against moment 0; error bars are above the curve of the L-dopa/carbidopa plus opicapone condition; error bars are below the curve of the L-dopa/carbidopa/entacapone condition.