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Population pharmacodynamic modeling of levodopa in patients with Parkinson's disease receiving entacapone
Author(s) -
Trocóniz Iñaki F.,
Naukkarinen Tarja H.,
Ruottinen Hanna M.,
Rinne Urpo K.,
Gordin Ariel,
Karlsson Mats O.
Publication year - 1998
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1016/s0009-9236(98)90028-5
Subject(s) - entacapone , benserazide , levodopa , pharmacodynamics , carbidopa , population , medicine , decarboxylase inhibitor , pharmacokinetics , pharmacology , nonmem , parkinson's disease , crossover study , placebo , disease , alternative medicine , environmental health , pathology
Objective To assess the pharmacodynamics of levodopa among patients with Parkinson's disease showing end‐of‐dose fluctuations at different doses of entacapone. Methods Nineteen patients participated in a randomized, double‐blind phase II study with a crossover design. Doses of 50, 100, 200, or 400 mg entacapone or placebo were given with the patient's individual levodopa‐dopa decarboxylase inhibitor dose. Blood samples were withdrawn for pharmacokinetic analysis, and the clinical response was measured using the motor part of the Unified Parkinson's Disease Rating Scale. A population pharmacodynamic model was developed with the NONMEM program. Results A sigmoidal E max model with an effect compartment was used to relate plasma concentrations of levodopa with clinical response. In the population analysis two covariate relationships were found. The first was E 0 = 55.2 · [1 + 0.012 · (Dur − 13)], where E 0 is the initial motor Unified Parkinson's Disease Rating Scale score, and Dur is the duration of disease in years. The second was C 50(carbidopa) = 951 ng/ml; C 50(benserazide) = 1238 ng/ml, where C 50 is the steady‐state plasma concentration of levodopa eliciting half of maximum attainable effect, and carbidopa and benserazide are the dopa decarboxylase inhibitors given in the study. No effect of entacapone on clinical response beyond its influence on levodopa pharmacokinetics was found. Interindividual and interoccasion variabilities were estimated. Conclusions A population pharmacodynamic model for levodopa was built that took into account interindividual and intraindividual variability. The main finding was that entacapone does not alter the concentration‐effect curve of levodopa, suggesting that entacapone acts at the level of peripheral pharmacokinetics of levodopa and that plasma levels of 3‐ O ‐methyldopa have a negligible role in the pharmacodynamics of levodopa. Clinical Pharmacology & Therapeutics (1998) 64 , 106–116; doi: