Document Detail


Pharmacokinetic-pharmacodynamic modeling of levodopa in patients with advanced Parkinson disease.
MedLine Citation:
PMID:  20216409     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Urszula Adamiak; Maria Kaldonska; Gabriela Klodowska-Duda; Elzbieta Wyska; Krzysztof Safranow; Monika Bialecka; Barbara Gawronska-Szklarz
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Publication Detail:
Type:  Clinical Trial; Journal Article; Research Support, N.I.H., Extramural    
Journal Detail:
Title:  Clinical neuropharmacology     Volume:  33     ISSN:  1537-162X     ISO Abbreviation:  Clin Neuropharmacol     Publication Date:  2010 May 
Date Detail:
Created Date:  2010-05-26     Completed Date:  2010-08-31     Revised Date:  2013-11-25    
Medline Journal Info:
Nlm Unique ID:  7607910     Medline TA:  Clin Neuropharmacol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  135-41     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Age of Onset
Aged
Antiparkinson Agents / adverse effects,  pharmacokinetics*,  pharmacology*,  therapeutic use
Benserazide / adverse effects,  pharmacology,  therapeutic use
Benzophenones / pharmacology,  therapeutic use
Carbidopa / adverse effects,  pharmacology,  therapeutic use
Catechol O-Methyltransferase / antagonists & inhibitors
Dopa Decarboxylase / antagonists & inhibitors
Drug Combinations
Drug Therapy, Combination
Dyskinesias / drug therapy
Enzyme Inhibitors / adverse effects,  pharmacology,  therapeutic use
Female
Half-Life
Humans
Levodopa / adverse effects,  pharmacokinetics*,  pharmacology*,  therapeutic use
Male
Metabolic Clearance Rate / drug effects
Middle Aged
Models, Biological
Nitrophenols / pharmacology,  therapeutic use
Parkinson Disease / drug therapy,  metabolism*,  physiopathology
Severity of Illness Index
Tyrosine / analogs & derivatives,  blood
Grant Support
ID/Acronym/Agency:
2P05F02328//PHS HHS
Chemical
Reg. No./Substance:
0/Antiparkinson Agents; 0/Benzophenones; 0/Drug Combinations; 0/Enzyme Inhibitors; 0/Nitrophenols; 0/benserazide, levodopa drug combination; 0/carbidopa, levodopa drug combination; 42HK56048U/Tyrosine; 46627O600J/Levodopa; 762OS3ZEJU/Benserazide; CIF6334OLY/tolcapone; EC 2.1.1.6/Catechol O-Methyltransferase; EC 4.1.1.-/Dopa Decarboxylase; MNX7R8C5VO/Carbidopa; V3O7J20DWN/3-methoxytyrosine

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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