Interventions to achieve tonic exposure to levodopa: delaying or preventing the onset of motor complications.

Abstract

Variations in levodopa delivery and subsequent dopamine exposure may lead to motor fluctuations and dyskinesias in patients with Parkinson's disease, as the therapeutic window for levodopa narrows with disease progression. Long-term exposure to the oscillations in levodopa-derived dopamine also is suggested to cause postsynaptic changes within the dopaminergic system, leading to further reductions in the drug's efficacy. The need to extend the actions of levodopa led to the development of the catechol-O-methyltransferase (COMT) inhibitors, which are the newest agents introduced to manage the symptoms of Parkinson's disease. Entacapone and tolcapone are two potent, selective, and reversible COMT inhibitors that effectively augment levodopa's pharmacokinetics by increasing area under the plasma concentration versus time curve and plasma elimination half-life without significantly affecting peak levodopa concentrations. This enhanced pharmacokinetic effect results in marked improvements in patients' clinical response. In patients experiencing end-of-dose wearing-off, the addition of either entacapone or tolcapone led to improvements in "on" time, "off" time, and the Unified Parkinson's Disease Rating Scale scoring system, even though many patients already were receiving optimum dosages of various other antiparkinsonian drugs. In patients with stable responses to long-term levodopa, addition of tolcapone significantly reduced the onset of motor fluctuations. These data, combined with the potential for delaying the onset of motor fluctuations, suggest that COMT inhibition may enhance levodopa's short- and long-term efficacy.