Pharmacokinetic-pharmacodynamic modeling of levodopa in patients with advanced Parkinson disease.
OBJECTIVE
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.
Adamiak
Urszula
U
Departments of Pharmacokinetics and Therapeutic Drug Monitoring, Pomeranian Medical University, Szczecin, Poland.
Kaldonska
Maria
M
Klodowska-Duda
Gabriela
G
Wyska
Elzbieta
E
Safranow
Krzysztof
K
Bialecka
Monika
M
Gawronska-Szklarz
Barbara
B
D017668:Age of Onset; D000368:Aged; D000978:Antiparkinson Agents / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology* / Q000627:therapeutic use; D065105:Aromatic Amino Acid Decarboxylase Inhibitors; D001545:Benserazide / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D001577:Benzophenones / Q000494:pharmacology / Q000627:therapeutic use; D002230:Carbidopa / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D065098:Catechol O-Methyltransferase Inhibitors; D004338:Drug Combinations; D004359:Drug Therapy, Combination; D020820:Dyskinesias / Q000188:drug therapy; D004791:Enzyme Inhibitors / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D006207:Half-Life; D006801:Humans; D007980:Levodopa / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D008657:Metabolic Clearance Rate / Q000187:drug effects; D008875:Middle Aged; D008954:Models, Biological; D009596:Nitrophenols / Q000494:pharmacology / Q000627:therapeutic use; D010300:Parkinson Disease / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology; D012720:Severity of Illness Index; D000077867:Tolcapone; D014443:Tyrosine / Q000031:analogs & derivatives / Q000097:blood
D000978:Antiparkinson Agents; D065105:Aromatic Amino Acid Decarboxylase Inhibitors; D001577:Benzophenones; D065098:Catechol O-Methyltransferase Inhibitors; D004338:Drug Combinations; D004791:Enzyme Inhibitors; D009596:Nitrophenols; C005177:benserazide, levodopa drug combination; C009265:carbidopa, levodopa drug combination; D014443:Tyrosine; D007980:Levodopa; D001545:Benserazide; D000077867:Tolcapone; D002230:Carbidopa; C008404:3-methoxytyrosine