Journal
CLINICAL NEUROPHARMACOLOGY
Volume 33, Issue 3, Pages 135-141Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1097/WNF.0b013e3181d47849
Keywords
Parkinson Disease; pharmacokinetic-pharmakodynamic modeling; levodopa; tolcapone
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Funding
- Ministry of Science and Higher Education, Warsaw, Poland [2P05F02328]
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Objectives: The aims of the present study were to investigate the pharmacokinetic and pharmacodynamic (pk/pd) relationship of levodopa (L-dopa) in patients with advanced Parkinson disease (PD) and also to evaluate the effect of tolcapone on the pk/pd analysis of L-dopa in 1 patient with severe dyskinesias and fluctuations. Methods: The pharmacokinetics (plasma concentrations of L-dopa and 3-O-methyldopa [3-OMD]) and motor effects (global score of the Unified Parkinson's Disease Rating Scale-III) of a single dose of L-dopa (plus the peripheral decarboxylase inhibitor 1: 4) were determined in 14 patients with advanced PD. Patients were classified into 2 groups according to Hoehn and Yahr scale (stages 2 and 3). In 1 patient with severe dyskinesias and. fluctuations, pk/pd of L-dopa were evaluated before and after coadministration of tolcapone at 100 mg 2 times daily for 1 month. The pk/pd analysis was based on an estimate of the maximal response model with a semiparametric approach to effect site equilibrium. Results: The highest levels of L-dopa and 3-OMD were observed in patients with stage 3 of Hoehn and Yahr scale. We showed differences in the pk/pd parameters after coadministration of tolcapone in 1 patient as well as the clinical improvement. Univariate analysis showed some significant correlations (P < 0.05) between L-dopa pk/pd parameters and patients' age, duration of L-dopa treatment, and duration of the disease. Multivariate analysis adjusted for patients' age, sex, duration of the disease, and Hoehn and Yahr stage showed that presence of diphasic (dyskinesia-improvement-dyskinesia [DID]) dyskinesias was the only independent predictor of larger threshold level - EC50 (mean concentration at half maximal effect) of L-dopa (P = 0.034). Conclusions: The motor complications during long treatment therapy in patients with advanced PD especially with stage 3 Hoehn and Yahr scale were correlated to the higher plasma concentrations of L-dopa. In the presented study, patients with motor complications, especially with DID dyskinesias, exhibited a larger threshold level (EC50). The clinical improvement of a patient who received L-dopa and tolcapone can be explained by tolcapone-induced changes of peripheral and central L-dopa pharmacokinetics, which led to a decrease of L-dopa EC50 and 3-OMD concentrations. Our data indicate that pk/pd analysis may be helpful for monitoring the efficiency of therapeutic strategy applied in PD patients.
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