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

ABSTRACT: 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??g?ml(-1) additive error) vs.?LC-oral (29% proportional error, 0.59??g?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.

SUBMITTER: Othman AA 

PROVIDER: S-EPMC4168384 | biostudies-literature | 2014 Jul

REPOSITORIES: biostudies-literature