Population pharmacokinetics of levodopa in subjects with advanced Parkinson's disease: levodopa-carbidopa intestinal gel infusion vs. oral tablets

Br J Clin Pharmacol. 2014 Jul;78(1):94-105. doi: 10.1111/bcp.12324.


Aims: 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.

Keywords: Duodopa; Parkinson's disease; intestinal gel; levodopa; population pharmacokinetics.

Publication types

  • Clinical Trial, Phase I
  • Clinical Trial, Phase III
  • Multicenter Study

MeSH terms

  • Administration, Oral
  • Adult
  • Aged
  • Aged, 80 and over
  • Antiparkinson Agents / administration & dosage
  • Antiparkinson Agents / blood
  • Antiparkinson Agents / pharmacokinetics
  • Biological Availability
  • Carbidopa / administration & dosage*
  • Carbidopa / blood
  • Carbidopa / pharmacokinetics
  • Double-Blind Method
  • Drug Combinations
  • Female
  • Gels
  • Humans
  • Infusions, Parenteral
  • Levodopa / administration & dosage*
  • Levodopa / blood
  • Levodopa / pharmacokinetics*
  • Male
  • Middle Aged
  • Models, Biological*
  • Parkinson Disease / blood
  • Parkinson Disease / drug therapy*
  • Tablets


  • Antiparkinson Agents
  • Drug Combinations
  • Gels
  • Tablets
  • Levodopa
  • Carbidopa