Intermittent vs Continuous Levodopa Administration in Patients With Advanced Parkinson Disease: A Clinical and Pharmacokinetic Study

Abstract

BACKGROUND: Levodopa-related motor complications can be an important source of disability for patients with advanced Parkinson disease. Current evidence suggests that these motor complications are related to the relatively short half-life of levodopa and its potential to induce pulsatile stimulation of striatal dopamine receptors. Motor complications can be diminished with a continuous infusion of levodopa. OBJECTIVE: To investigate the specific pharmacokinetic changes associated with the benefits of levodopa infusion. DESIGN: We performed an open-label study in 6 patients with Parkinson disease who experienced severe motor complications while receiving standard oral formulations of levodopa/carbidopa. Patients were subsequently treated for 6 months with continuous daytime intraintestinal infusions of levodopa methyl ester. Levodopa pharmacokinetic studies were performed at baseline and 6 months in 3 of these patients. RESULTS: Compared with treatment with intermittent doses of a standard oral formulation of levodopa, continuous infusion provided significant improvement in both "off periods" and dyskinesia. Results of plasma pharmacokinetic studies demonstrated that compared with oral administration, continuous levodopa infusion was associated with a significant increase in the levodopa area under the curve and avoided the low plasma trough levels seen with oral drug administration. CONCLUSIONS: This study confirms that a continuous levodopa infusion is associated with reduced motor complications compared with the standard oral formulation of the drug in patients with advanced PD. Pharmacokinetic studies demonstrate that reduced motor complications are associated with avoiding low plasma levodopa trough levels and are not adversely affected by relatively high plasma levodopa concentrations. We propose that if levodopa/carbidopa could be administered orally in a manner that mirrors the pharmacokinetic pattern of the infusion, it might lead to a similar reduction in motor complications.