title: A pharmacokinetic-pharmacodynamic model for duodenal levodopa infusion.
abstract: OBJECTIVE
  The purpose of this work was to identify and estimate a population pharmacokinetic- pharmacodynamic model for duodenal infusion of a levodopa/carbidopa gel (Duodopa) to examine pharmacological properties of this treatment.
  
  
  METHODS
  The modeling involved pooling data from 3 studies (on advanced Parkinson disease) and fixing some parameters to values found in literature. The first study involved 12 patients studied on 3 occasions each and was previously published. The second study involved 3 patients on 2 occasions. A bolus dose was given after a washout during night. Plasma samples and motor ratings (clinical assessment of motor function on a 7-point treatment response scale ranging from "very off" to "very hyperkinetic") were collected until the clinical effect returned to baseline. The third study involved 5 patients on 3 occasions receiving 5 different dose levels. Different structural models were evaluated using the nonlinear mixed-effects modeling program NONMEM VI. Population mean parameter values, and interindividual, interoccasion, and residual variabilities were estimated.
  
  
  RESULTS
  Absorption of the levodopa/carbidopa gel can be adequately described with first-order absorption with bioavailability and lag time. Estimated population parameter values were a mean absorption time of 28.5 minutes, a lag time of 2.9 minutes, and a bioavailability of 88%. The pharmacodynamic model for motor ratings had the following population values: a half-life of effect delay of 21 minutes, a concentration at 50% effect of 1.55 mg/L, an Emax of 2.39 U on the treatment response scale, and a sigmoidicity of the Emax function of 11.6.
  
  
  CONCLUSIONS
  For the typical unmedicated subject, it will take 51.4 minutes until the peak levodopa effect is reached after a bolus dose. This delay is, like the magnitude of the effect, highly variable in this patient group. The residual error magnitudes of 20% for levodopa concentrations and 0.92 U (SD) for motor ratings indicate that the models developed provide predictions of a relevant quality. The developed model may be a first step toward model-guided treatment individualization of duodenal infusion of levodopa.
authors.affiliation: Department of Medical Sciences, Biomedical Informatics and Engineering, Uppsala University, Uppsala, Sweden. jwe@du.se
authors.forename: Jerker
authors.initials: J
authors.lastname: Westin
authors.forename: Dag
authors.initials: D
authors.lastname: Nyholm
authors.forename: Sven
authors.initials: S
authors.lastname: Pålhagen
authors.forename: Thomas
authors.initials: T
authors.lastname: Willows
authors.forename: Torgny
authors.initials: T
authors.lastname: Groth
authors.forename: Mark
authors.initials: M
authors.lastname: Dougherty
authors.forename: Mats O
authors.initials: MO
authors.lastname: Karlsson
mesh_terms: D000368:Aged; D000978:Antiparkinson Agents / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D004386:Duodenum / Q000187:drug effects / Q000378:metabolism; D005260:Female; D006801:Humans; D007260:Infusion Pumps; D007980:Levodopa / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D008297:Male; D008875:Middle Aged; D008956:Models, Chemical; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D017711:Nonlinear Dynamics; D010300:Parkinson Disease / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D013997:Time Factors
chemical_list: D000978:Antiparkinson Agents; D007980:Levodopa