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Pharmacokinetic-pharmacodynamic modeling of levodopa in patients with advanced Parkinson disease.
Clin Neuropharmacol. 2010 May; 33(3):135-41.CN

Abstract

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+Show Affiliations

Departments of Pharmacokinetics and Therapeutic Drug Monitoring, Pomeranian Medical University, Szczecin, Poland.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Clinical Trial
Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

20216409

Citation

Adamiak, Urszula, et al. "Pharmacokinetic-pharmacodynamic Modeling of Levodopa in Patients With Advanced Parkinson Disease." Clinical Neuropharmacology, vol. 33, no. 3, 2010, pp. 135-41.
Adamiak U, Kaldonska M, Klodowska-Duda G, et al. Pharmacokinetic-pharmacodynamic modeling of levodopa in patients with advanced Parkinson disease. Clin Neuropharmacol. 2010;33(3):135-41.
Adamiak, U., Kaldonska, M., Klodowska-Duda, G., Wyska, E., Safranow, K., Bialecka, M., & Gawronska-Szklarz, B. (2010). Pharmacokinetic-pharmacodynamic modeling of levodopa in patients with advanced Parkinson disease. Clinical Neuropharmacology, 33(3), 135-41. https://doi.org/10.1097/WNF.0b013e3181d47849
Adamiak U, et al. Pharmacokinetic-pharmacodynamic Modeling of Levodopa in Patients With Advanced Parkinson Disease. Clin Neuropharmacol. 2010;33(3):135-41. PubMed PMID: 20216409.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Pharmacokinetic-pharmacodynamic modeling of levodopa in patients with advanced Parkinson disease. AU - Adamiak,Urszula, AU - Kaldonska,Maria, AU - Klodowska-Duda,Gabriela, AU - Wyska,Elzbieta, AU - Safranow,Krzysztof, AU - Bialecka,Monika, AU - Gawronska-Szklarz,Barbara, PY - 2010/3/11/entrez PY - 2010/3/11/pubmed PY - 2010/9/2/medline SP - 135 EP - 41 JF - Clinical neuropharmacology JO - Clin Neuropharmacol VL - 33 IS - 3 N2 - 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. SN - 1537-162X UR - https://www.unboundmedicine.com/medline/citation/20216409/Pharmacokinetic_pharmacodynamic_modeling_of_levodopa_in_patients_with_advanced_Parkinson_disease_ L2 - http://dx.doi.org/10.1097/WNF.0b013e3181d47849 DB - PRIME DP - Unbound Medicine ER -