A. Marsot (1), B. Imbert (2), JC. Alvarez (3), S. Grassin-Delyle (3), I. Jaquet (2), C. Lançon (2), N. Simon (1,2)
(1) Service de Pharmacologie Clinique, Hôpital Timone, APHM, Aix Marseille Université, France, (2) Service d'Addictologie, Hôpital Sainte Marguerite, APHM, Aix Marseille Université, France, (3) Laboratoire de Pharmacologie-Toxicologie, CHU Raymond Poincaré, Garches, France
Objectives: Baclofen is a GABA-B receptor agonist used in the treatment of spasticity. Recently, baclofen is used out of its label to decrease craving of alcoholic patients. Its optimal use in these patients requires further pharmacokinetic informations. The objective of this study was to characterize the pharmacokinetics of baclofen in alcohol dependent patients. Randomized clinical trials are ongoing to evaluate the efficacy for this new indication.
Methods: 37 outpatients (weight: 74.0 kg [42.0 – 104.0]; Age: 49 years [31 – 68]) followed in the addictology unit, were studied. Total mean dose of 77.9 mg (30 – 240) per day was administered by oral route. Therapeutic drug monitoring allowed the measurement of 139 plasma concentrations. The following covariates were evaluated: demographic data (age, body weight, height, sex), biological data (creatinine, urea, AST, ALT, albumin, PR, VGM, PAL, CDT, GGT) and tobacco consumption (number of cigarettes and Fagerstrom test). Pharmacokinetic analysis was performed by using a non-linear mixed-effect population model (NONMEM 7.2 software).
Results: Data were modelled with a one-compartment pharmacokinetic model. The population typical mean (percent relative standard error (%RSE)) values for clearance (CL), apparent volume of distribution (V) and constant of absorption (Ka) were 10.3 L/h (6.3%), 81.1 L (12.1%) and 3.61 h-1 (50.4%), respectively. The interindividual variability of CL (%RSE) and V (%RSE), and residual variability (%RSE) were 53.9% (24.7%), 73.5% (45.5%) and 0.096 mg/l (20.0%), respectively.
Conclusions: Baclofen exhibited a linear pharmacokinetic with a proportional relationship from 30 to 240 mg per day, the dose range currently used in alcoholic patients. A wide inter-patient variability was observed which could not be explained by the covariates. This high variability of baclofen exposure may explain the lack of response observed for some patients.
Reference: PAGE 22 (2013) Abstr 2742 [www.page-meeting.org/?abstract=2742]
Poster: CNS