Optimizing levodopa therapy for Parkinson's disease with levodopa/carbidopa/entacapone: implications from a clinical and patient perspective

Abstract

After 40 years of clinical experience, levodopa remains the gold standard treatment for Parkinson's disease (PD) despite the recent emergence of a host of new therapies. Some physicians are cautious when prescribing levodopa because of its association with motor complications. Evidence now suggests that levodopa-associated complications are a result of deep troughs in delivery of levodopa to the brain caused by the short plasma half-life of conventional levodopa formulations (levodopa and a dopa decarboxylase inhibitor [DDCI]). Dosing strategies, such as dose increases and dose fractionation, may be effective in the short term. For the longer-term, levodopa/carbidopa/entacapone provides pharmacokinetically optimized levodopa therapy that significantly increases the plasma half-life and bioavailability of levodopa, providing more consistent plasma levodopa levels without deep troughs. Evidence from clinical trials in PD patients experiencing re-emergence of symptoms due to wearing-off has consistently shown that levodopa/DDCI and entacapone significantly increases ON-time and affords greater functionality, as measured by the Unified Parkinson's Disease Rating Scale (UPDRS) with conventional levodopa. These trials have also shown that levodopa/DDCI and entacapone is generally well tolerated, with notable adverse events including worsening dyskinesia, nausea and diarrhea. Patients experiencing re-emergence of symptoms due to wearing-off may benefit from optimized levodopa therapy with levodopa/carbidopa/entacapone.

Keywords: Stalevo; dyskinesia; entacapone; levodopa; wearing-off.

Figure 1

Plasma levodopa profiles with conventional levodopa dosing strategies. Schematic depicting plasma levodopa levels in Parkinson’s disease patients experiencing re-emergence of symptoms due to wearing-off achieved by (A) increasing the daily levodopa/carbidopa dose from 300 mg/day to 450 mg/day; (B)increasing the frequency of levodopa/carbidopa dosing from 3 times/day to 5 times/day.

Figure 2

Plasma levodopa profile with levodopa/carbidopa/entacapone versus levodopa/carbidopa. Treatment with levodopa/carbidopa/entacapone 3 times/day significantly improves troughs in plasma levodopa levels compared with equivalent doses of levodopa/carbidopa in patients with Parkinson’s disease; *p < 0.05; ^†p < 0.01; ^‡p < 0.001; SEM, standard error of the mean.

Figure 3

Efficacy of levodopa/dopa decarboxylase inhibitor and entacapone therapy in the short-term. Treatment with levodopa/DDCI and entacapone is associated with significant improvements in functional control as determined by UPDRS total, ADL and motor scores compared with levodopa/DDCI and placebo over 6 months. *p < 0.01; ^†p < 0.05. Abbreviations: UPDRS, Unified Parkinson’s Disease Rating Scale; ADL, activities of daily living; DDCI, dopa decarboxylase inhibitor.

Figure 4

Efficacy of levodopa/dopa decarboxylase inhibitor and entacapone therapy in the long-term. Functionality is maintained over three years with levodopa/DDCI and entacapone. ^‡p =not significant. Abbreviations: UPDRS, Unified Parkinson’s Disease Rating Scale; ADL, activities of daily living; DDCI, dopa decarboxylase inhibitor.

Figure 5

Effect of levodopa/carbidopa/entacapone on quality of life in patients with stable Parkinson’s disease. Treatment with levodopa/carbidopa/entacapone is associated with significant benefits in terms of quality of life compared with levodopa/carbidopa, as determined by the Parkinson’s disease questionnaire-8. Abbreviations: PDQ, Parkinson’s disease questionnaire; NS, not significant; Q, question.