title: A combined pharmacokinetic/pharmacodynamic model of levodopa motor response and dyskinesia in Parkinson's disease patients.
abstract: OBJECTIVE
  Levodopa is the reference treatment for Parkinson's disease. However, after several years of treatment, dyskinesia may occur and strategies to overcome this side effect still need to be explored. We identified a unique population pharmacokinetic/pharmacodynamic model in Parkinson's disease to investigate the relationship and dissociability of motor response and dyskinesia.
  
  
  METHODS
  Thirty parkinsonian patients (Hoehn and Yahr stages 3-4), treated with levodopa and suffering from peak-dose dyskinesia, were included in a prospective open-label study. They received a single dose of levodopa equal to 150 % of their usual daily dose. Blood samples, motor evaluations (UPDRS III scale) and peak-dose dyskinesia (Goetz scale) were examined after administration. A population pharmacokinetic/pharmacodynamic (PK/PD) model was developed using NONMEM software.
  
  
  RESULTS
  Pharmacokinetic analysis identified a one-compartment model with the following parameter values [bootstrap 95 % CI]: absorption rate constant (KA) 1.86 1/h [1.08-3.25], clearance 36.6 L/h [31.3-42.8], and volume of distribution 42.9 L [34.3-52.3]. Between-subject variability was 122 % [71-183] and 38 % [26-47] for KA and clearance, respectively. Residual variability was 1120 μg/L [886-1290]. UPDRS III and dyskinesia were best described with an effect compartment and similar KE0 values of 1.37 1/h [1.01-1.77]. For UPDRS III, the E0, EC50, Emax, and Hill coefficient were 31.4 [28.4-35.3], 1410 μg/L [1200-1700], 0.72 [0.71-0.75], and 4.26 [3.20-5.58], respectively. For dyskinesia, the EC50 and Emax were 6280 μg/L [3420-37,900] and 17.9 [12.3-80.8], respectively. Residual variability was 3.15 [2.75-3.53] for UPDRS III and 2.66 [1.94-3.51] for dyskinesia. No covariates influenced the parameters.
  
  
  CONCLUSIONS
  In patients treated with levodopa and suffering from dyskinesia, the motor response and dyskinesia have close onsets and duration effects. Maximal motor response tends to be inevitably associated with dyskinesia.
authors.affiliation: Service de Pharmacologie Clinique, AP-HM, Hôpital Sainte Marguerite, CAP-TV, 13274, Marseille, France. nicolas.Simon@ap-hm.fr.|Aix-Marseille Université, INSERM UMR_S 912 (SESSTIM), IRD, 13385, Marseille, France. nicolas.Simon@ap-hm.fr.
authors.forename: N
authors.initials: N
authors.lastname: Simon
authors.affiliation: Service de neurologie, Centre Hospitalier Intercommunal Aix Pertuis, 13613, Aix-en-Provence, France.|Laboratoire Parole et langage, Aix-Marseille Université, UMR CNRS 7309, 13003, Marseille, France.
authors.forename: F
authors.initials: F
authors.lastname: Viallet
authors.affiliation: Service de Pharmacologie Clinique, AP-HM, Hôpital Sainte Marguerite, CAP-TV, 13274, Marseille, France.
authors.forename: A
authors.initials: A
authors.lastname: Boulamery
authors.affiliation: Service de Neurologie, CHU Timone, Marseille, France.
authors.forename: A
authors.initials: A
authors.lastname: Eusebio
authors.affiliation: Service de neurologie, Centre Hospitalier Intercommunal Aix Pertuis, 13613, Aix-en-Provence, France.
authors.forename: D
authors.initials: D
authors.lastname: Gayraud
authors.affiliation: Service de Neurologie, CHU Timone, Marseille, France.
authors.forename: J-P
authors.initials: JP
authors.lastname: Azulay
mesh_terms: D000368:Aged; D000978:Antiparkinson Agents / Q000009:adverse effects* / Q000627:therapeutic use*; D004409:Dyskinesia, Drug-Induced / Q000209:etiology*; D005260:Female; D006801:Humans; D007980:Levodopa / Q000009:adverse effects* / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D010300:Parkinson Disease / Q000188:drug therapy*; D011446:Prospective Studies
chemical_list: D000978:Antiparkinson Agents; D007980:Levodopa
keywords: Levodopa; NONMEM; Parkinson’s dyskinesia; Pharmacodynamics; Population pharmacokinetics