title: Population pharmacokinetics of levodopa in subjects with advanced Parkinson's disease: levodopa-carbidopa intestinal gel infusion vs. oral tablets.
abstract: OBJECTIVE
  Levodopa-carbidopa intestinal gel (LCIG) provides continuous levodopa-carbidopa delivery through intrajejunal infusion. This study characterized the population pharmacokinetics of levodopa following a 16 h jejunal infusion of LCIG or frequent oral administration of levodopa-carbidopa tablets (LC-oral) in subjects with advanced Parkinson's disease (PD).
  
  
  METHODS
  A non-linear mixed-effects model of levodopa pharmacokinetics was developed using serial plasma concentrations from an LCIG phase 1 study and a phase 3 double-blind, double-dummy study of the efficacy and safety of LCIG compared with LC-oral in advanced PD patients (n = 68 for model development; 45 on LCIG and 23 on LC-oral). The final model was internally evaluated using stochastic simulations and bootstrap and externally evaluated using sparse pharmacokinetic data from 311 subjects treated in a long term safety study of LCIG.
  
  
  RESULTS
  The final model was a two compartment model with a transit compartment for absorption, first order elimination, bioavailability for LCIG (97%; confidence interval = 95% to 98%) relative to LC-oral, different first order transit absorption rate constants (LCIG = 9.2 h(-1) vs. LC-oral = 2.4 h(-1) ; corresponding mean absorption time of 7 min for LCIG vs. 25 min for LC-oral) and different residual (intra-subject) variability for LCIG (15% proportional error, 0.3 μg ml(-1) additive error) vs. LC-oral (29% proportional error, 0.59 μg ml(-1) additive error). Estimated oral clearance and steady-state volume of distribution for levodopa were 24.8 l h(-1) and 131 l, respectively.
  
  
  CONCLUSIONS
  LCIG administration results in faster absorption, comparable levodopa bioavailability and significantly reduced intra-subject variability in levodopa concentrations relative to LC-oral administration.
authors.affiliation: Clinical Pharmacology and Pharmacometrics, AbbVie, North Chicago, IL, USA; Department of Pharmaceutics, Faculty of Pharmacy, Cairo University, Cairo, Egypt.
authors.forename: Ahmed A
authors.initials: AA
authors.lastname: Othman
authors.forename: Sandeep
authors.initials: S
authors.lastname: Dutta
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000978:Antiparkinson Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D001682:Biological Availability; D002230:Carbidopa / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics; D004311:Double-Blind Method; D004338:Drug Combinations; D005260:Female; D005782:Gels; D006801:Humans; D007263:Infusions, Parenteral; D007980:Levodopa / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D010300:Parkinson Disease / Q000097:blood / Q000188:drug therapy*; D013607:Tablets
chemical_list: D000978:Antiparkinson Agents; D004338:Drug Combinations; D005782:Gels; D013607:Tablets; D007980:Levodopa; D002230:Carbidopa
keywords: Duodopa; Parkinson's disease; intestinal gel; levodopa; population pharmacokinetics