Pharmacokinetic Considerations for the Use of Levodopa in the Treatment of Parkinson Disease: Focus on Levodopa/Carbidopa/Entacapone for Treatment of Levodopa-Associated Motor Complications

Parkinson disease (PD) is a progressive, disabling, neurodegenerative disorder characterized by both motor and nonmotor symptoms. Monoamine oxidase B inhibitors, dopamine agonists, N-methyl-D-aspartate antagonists and levodopa (LD), with its various formulations and administration modes, mainly improve the motor symptoms in PD, which are thought to be related to decreased dopamine levels in the brain. Of these therapeutic drug options, LD represents the most effective and best tolerated compound when it is administered several times a day. Pharmacokinetic trials of oral LD/dopa decarboxylase inhibitor (DDCI) formulations with and without the catechol-O-methyltransferase inhibitor, entacapone, showed that repeated administration with entacapone causes an increase in both the maximum concentration (C-max) and time to C-max (T-max) of LD. In addition, gastrointestinal motility may also impact plasma LD behavior. These peripheral components of LD metabolism contribute to the onset of motor complications, which are predominantly associated with LD/DDCI owing to its short plasma half-life. The increase in T-max is related to a slower increase in plasma LD concentrations after repeated LD/DDCI intake, which may also increase the risk of wearing off. An elevation in C-max after reiterated LD intake increases the risk of peak-dose dyskinesia. Therefore, it may be useful to start with higher doses of LD formulations in the morning and then to titrate with different LD doses during the day according to the individual patient's motor behavior, which is particularly characterized by the onset of motor complications, such as off periods and dyskinesia, in more advanced stages of PD.