Population pharmacokinetics and pharmacodynamics of oral levodopa in parkinsonian patients

E. J. Triggs, B. G. Charles, M. Contin, P. Martinelli, P. Cortelli, R. Riva, F. Albani, A. Baruzzi

Research output: Contribution to journalArticle

Abstract

Objective: The population pharmacokinetics and pharmacodynamics of a standardised oral test dose of levodopa have been determined in patients with mild to severe Parkinson's disease using parametric, nonlinear mixed effect modelling with the program NONMEM. Levodopa plasma concentration data and motor effect behaviour (tapping times) were obtained from 46 patients, for whom a total of 970 observations were available (approximately 21 pharmacokinetic and pharmacodynamic observations per patient). The pharmacokinetic-pharmacodynamic model used was a one-compartment first-order absorption model linked to the sigmoid E(Max) representation of the Hill equation via an equilibration rate-constant, ke0. The model was also tested via a reduction in the number of pharmacokinetic and pharmacodynamic data points to a total of four to eight per patient. Results: In the final regression models the Hoehn and Yahr (HY) status of the patient and duration of disease (DUR) were found to be important determinants of the pharmacodynamic parameters for levodopa. The pharmacokinetic parameters were not significantly affected by any covariates. A test group of 16 additional parkinsonian patients was used to evaluate the predictive performance of the population parameters. The predictive performance of the pharmacokinetic-pharmacodynamic modelling using the full and reduced data sets was evaluated in NONMEM using posthoc, Bayesian forecasting. Statistically insignificant bias existed among predicted and observed levodopa concentrations, whereas the pharmacodynamic model underpredicted the observed tapping times. There was little difference in the pharmacokinetic-pharmacody namic predictive performance among results for the full and the reduced data sets. Conclusion: In a clinical setting knowledge of the population pharmacokinetic and pharmacodynamic parameters for oral levodopa may prove useful in estimating the duration of the drug's beneficial motor activity in patients with mild to severe Parkinson's disease (Hoehn and Yahr status I-IV).

Original languageEnglish
Pages (from-to)59-67
Number of pages9
JournalEuropean Journal of Clinical Pharmacology
Volume51
Issue number1
DOIs
Publication statusPublished - 1996

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Levodopa
Pharmacokinetics
Population
Parkinson Disease
Sigmoid Colon
Motor Activity
Pharmaceutical Preparations

Keywords

  • Levodopa
  • NONMEM
  • Parkinson's disease
  • Pharmacodynamics
  • Pharmacokinetics

ASJC Scopus subject areas

  • Pharmacology (medical)
  • Pharmacology, Toxicology and Pharmaceutics(all)

Cite this

Population pharmacokinetics and pharmacodynamics of oral levodopa in parkinsonian patients. / Triggs, E. J.; Charles, B. G.; Contin, M.; Martinelli, P.; Cortelli, P.; Riva, R.; Albani, F.; Baruzzi, A.

In: European Journal of Clinical Pharmacology, Vol. 51, No. 1, 1996, p. 59-67.

Research output: Contribution to journalArticle

Triggs, E. J. ; Charles, B. G. ; Contin, M. ; Martinelli, P. ; Cortelli, P. ; Riva, R. ; Albani, F. ; Baruzzi, A. / Population pharmacokinetics and pharmacodynamics of oral levodopa in parkinsonian patients. In: European Journal of Clinical Pharmacology. 1996 ; Vol. 51, No. 1. pp. 59-67.
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abstract = "Objective: The population pharmacokinetics and pharmacodynamics of a standardised oral test dose of levodopa have been determined in patients with mild to severe Parkinson's disease using parametric, nonlinear mixed effect modelling with the program NONMEM. Levodopa plasma concentration data and motor effect behaviour (tapping times) were obtained from 46 patients, for whom a total of 970 observations were available (approximately 21 pharmacokinetic and pharmacodynamic observations per patient). The pharmacokinetic-pharmacodynamic model used was a one-compartment first-order absorption model linked to the sigmoid E(Max) representation of the Hill equation via an equilibration rate-constant, ke0. The model was also tested via a reduction in the number of pharmacokinetic and pharmacodynamic data points to a total of four to eight per patient. Results: In the final regression models the Hoehn and Yahr (HY) status of the patient and duration of disease (DUR) were found to be important determinants of the pharmacodynamic parameters for levodopa. The pharmacokinetic parameters were not significantly affected by any covariates. A test group of 16 additional parkinsonian patients was used to evaluate the predictive performance of the population parameters. The predictive performance of the pharmacokinetic-pharmacodynamic modelling using the full and reduced data sets was evaluated in NONMEM using posthoc, Bayesian forecasting. Statistically insignificant bias existed among predicted and observed levodopa concentrations, whereas the pharmacodynamic model underpredicted the observed tapping times. There was little difference in the pharmacokinetic-pharmacody namic predictive performance among results for the full and the reduced data sets. Conclusion: In a clinical setting knowledge of the population pharmacokinetic and pharmacodynamic parameters for oral levodopa may prove useful in estimating the duration of the drug's beneficial motor activity in patients with mild to severe Parkinson's disease (Hoehn and Yahr status I-IV).",
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