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Population pharmacokinetics of levodopa in subjects with advanced P arkinson's disease: levodopa‐carbidopa intestinal gel infusion vs . oral tablets
Author(s) -
Othman Ahmed A.,
Dutta Sandeep
Publication year - 2014
Publication title -
british journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.216
H-Index - 146
eISSN - 1365-2125
pISSN - 0306-5251
DOI - 10.1111/bcp.12324
Subject(s) - levodopa , pharmacokinetics , bioavailability , carbidopa , oral administration , parkinson's disease , medicine , population , pharmacology , disease , environmental health
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 P arkinson'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.