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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

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

Othman Ahmed A AA Dutta Sandeep S

British journal of clinical pharmacology 20140701 1

<h4>Aims</h4>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).<h4>Methods</h4>A non-linear mixed-effects model of levodopa pharmacokinetics was developed using serial plasma concentrations from a ...[more]

PMID: 24433449

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Project description:BackgroundTesting and titration of the right levodopa equivalent dose are usually performed during a hospital admission. However, optimal dose titration in people with Parkinson's disease (PwPs) may depend on home environment, emotional stress, and physical activity of everyday life.ObjectiveFirstly, to evaluate the feasibility and safety of a home-based LCIG titration program and patients'/caregivers' satisfaction. Secondly, to identify barriers and facilitators for home-based titration.MethodThis study assesses the feasibility and safety of home-based titration of levodopa duodenal infusions with the use of self-reported evaluation questionnaires with open-ended questions included, registration of total time used, and number of contacts/visits. A telemedicine solution was used to remotely monitor the patients, adjust treatment, and provide support and guidance to patients and caregivers.ResultsTen of 12 PwPs (5 females and 7 males) completed the total titration program. Eight of the 12 PwPs were dependent on help. These 8 PwPs also had a high burden of nonmotor symptoms (NMS). Cognitive impairments varied in severity (range 16-30). Time spent with home visits was on average 93.4 minutes (ranging from 35 to 180 minutes), and the length of the total titration (LCIG initiation to termination of titration) was on average 3.4 days with 2-5 (mean 3.2) contacts/visits with PD team members. The average score on the satisfaction evaluation questionnaires was lower in the caregiver group (mean 31.8) than the PwP outcome (mean 36.2).ConclusionsTelehealth-assisted home-based titration programs are feasible due to the length of the titration period, number of contacts, and time spent in PwPs' private homes, are rated satisfactory and safe by PwPs and caregivers, and may be a substitute for in-hospital treatment. Clinical recommendations including facilitators and barriers from a patient/caregiver perspective are displayed. This trial is registered with NCT4196647.

Dataset Information

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

Publications

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

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