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Population pharmacodynamic modeling of levodopa in patients with Parkinson's disease receiving entacapone.
Clin Pharmacol Ther. 1998 Jul; 64(1):106-16.CP

Abstract

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 Blood samples were withdrawn for pharmacokinetic analysis, and the clinical response was measured using the motor part of the Unified Parkinson's Disease Rating Scale.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 Emax 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 E0 = 55.2, [1 + 0.012. (Dur-13)], where E0 is the initial motor Unified Parkinson's Disease Rating Scale score, and Dur is the duration of disease in years. The second was C50(carbidopa) = 951 ng/ml; C50(benserazide) = 1238 ng/ml, where C50 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.

Authors+Show Affiliations

Department of Pharmacy, School of Pharmacy, University of Navarra, Pamplona, Spain.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Clinical Trial
Clinical Trial, Phase II
Journal Article
Randomized Controlled Trial

Language

eng

PubMed ID

9695725

Citation

Trocóniz, I F., et al. "Population Pharmacodynamic Modeling of Levodopa in Patients With Parkinson's Disease Receiving Entacapone." Clinical Pharmacology and Therapeutics, vol. 64, no. 1, 1998, pp. 106-16.
Trocóniz IF, Naukkarinen TH, Ruottinen HM, et al. Population pharmacodynamic modeling of levodopa in patients with Parkinson's disease receiving entacapone. Clin Pharmacol Ther. 1998;64(1):106-16.
Trocóniz, I. F., Naukkarinen, T. H., Ruottinen, H. M., Rinne, U. K., Gordin, A., & Karlsson, M. O. (1998). Population pharmacodynamic modeling of levodopa in patients with Parkinson's disease receiving entacapone. Clinical Pharmacology and Therapeutics, 64(1), 106-16.
Trocóniz IF, et al. Population Pharmacodynamic Modeling of Levodopa in Patients With Parkinson's Disease Receiving Entacapone. Clin Pharmacol Ther. 1998;64(1):106-16. PubMed PMID: 9695725.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Population pharmacodynamic modeling of levodopa in patients with Parkinson's disease receiving entacapone. AU - Trocóniz,I F, AU - Naukkarinen,T H, AU - Ruottinen,H M, AU - Rinne,U K, AU - Gordin,A, AU - Karlsson,M O, PY - 1998/8/8/pubmed PY - 1998/8/8/medline PY - 1998/8/8/entrez SP - 106 EP - 16 JF - Clinical pharmacology and therapeutics JO - Clin Pharmacol Ther VL - 64 IS - 1 N2 - 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 Emax 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 E0 = 55.2, [1 + 0.012. (Dur-13)], where E0 is the initial motor Unified Parkinson's Disease Rating Scale score, and Dur is the duration of disease in years. The second was C50(carbidopa) = 951 ng/ml; C50(benserazide) = 1238 ng/ml, where C50 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. SN - 0009-9236 UR - https://www.unboundmedicine.com/medline/citation/9695725/Population_pharmacodynamic_modeling_of_levodopa_in_patients_with_Parkinson's_disease_receiving_entacapone_ L2 - https://onlinelibrary.wiley.com/resolve/openurl?genre=article&sid=nlm:pubmed&issn=0009-9236&date=1998&volume=64&issue=1&spage=106 DB - PRIME DP - Unbound Medicine ER -