• Ahmed A Othman and Sandeep Dutta.
• Clinical Pharmacology and Pharmacometrics, AbbVie, North Chicago, IL, USA; Department of Pharmaceutics, Faculty of Pharmacy, Cairo University, Cairo, Egypt.
• Br J Clin Pharmacol. 2014 Jul 1;78(1):94-105.

AimsLevodopa-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).MethodsA 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.ResultsThe 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.ConclusionsLCIG administration results in faster absorption, comparable levodopa bioavailability and significantly reduced intra-subject variability in levodopa concentrations relative to LC-oral administration.© 2014 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of The British Pharmacological Society.

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