POPULATION PHARMACOKINETICS AND PHARMACODYNAMICS OF ORAL LEVODOPA IN PARKINSONIAN-PATIENTS

Objective: The population pharmacokinetics and pharmacodynamics of a s tandardised oral test dose of levodopa have been determined in patient s with mild to severe Parkinson's disease using parametric, nonlinear mixed effect modelling with the program NONMEM. Levodopa plasma concen tration 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-co mpartment first-order absorption model linked to the sigmoid E(Max) re presentation of the Hill equation via an equilibration rate-constant, ke(0), The model was also tested via a reduction in the number of phar macokinetic and pharmacodynamic data points to a total of four to eigh t per patient. Results: In the final regression models the Hoehn and Y ahr (HY) status of the patient and duration of disease (DUR) were foun d to be important determinants of the pharmacodynamic parameters for l evodopa. The pharmacokinetic parameters were not significantly affecte d by any covariates. A test group of 16 additional parkinsonian patien ts was used to evaluate the predictive performance of the population p arameters. The predictive performance of the pharmacokinetic-pharmacod ynamic modelling using the full and reduced data sets was evaluated in NONMEM using posthoc, Bayesian forecasting. Statistically insignifica nt bias existed among predicted and observed levodopa concentrations, whereas the pharmacodynamic model underpredicted the observed tapping times. There was little difference in the pharmacokinetic-pharmacodyna mic predictive performance among results for the full and the reduced data sets. Conclusion: In a clinical setting knowledge of the populati on pharmacokinetic and pharmacodynamic parameters for oral levodopa ma y prove useful in estimating the duration of the drug's beneficial mot or activity in patients with mild to severe Parkinson's disease (Hoehn and Yahr status I-IV).