Clinical pharmacokinetics of levodopa and relevant add-on therapies for Parkinson's disease

Parkinson's disease is a chronic neurodegenerative disease entity characterized by heterogeneity of symptoms and progression. Levodopa is an efficacious and well tolerated dopamine substituting drug for its therapy. Its O-methylation and generation of 3-O-methyldopa is enhanced by levodopa/dopa decarboxylase inhibitor formulations. Additional inhibition of catechol-O-methyltransferase is the relevant add on therapy for levodopa application. This pharmacologic approach increases the plasma appearance of levodopa and reduces 3-O-methyldopa synthesis. Available marketed compounds are entacapone, tolcapone and opicapone. Data on their effects on levodopa pharmacokinetics in patients are rare.

This review describes the impact of this add-on therapy on the pharmacokinetic profile of levodopa and 3-O-methyldopa in plasma. The rationale was to perform a comparison with data from previously published pharmacokinetic trials with a standardized one time intake of levodopa/carbidopa without and with the available catechol-O-methyltransferase inhibitors.

Results of this analysis identified opicapone as the most efficacious inhibitor of catechol-O-methyltransferase in terms of changes of levodopa plasma concentrations. Opicapone induced higher levodopa plasma levels compared with the ones following application of levodopa/carbidopa alone or combined with entacapone or tolcapone. Co-administration of opicapone with its once daily intake regimen may support the efficacy of subcutaneous and intrajejunal levodopa infusions.