Population pharmacokinetics of oral baclofen

Fundam Clin Pharmacol. 2017 Nov 1. doi: 10.1111/fcp.12330. [Epub ahead of print]

Population pharmacokinetics of oral baclofen at steady-state in alcoholic-dependent adult patients.

Chevillard L1, Sabo N2, Tod M3,4, Labat L1,2, Chasport C2, Chevaleyre C2, Thibaut F5, Barré J6, Azuar J5, Questel F1,5, Vorspan F1,5, Bloch V1, Bellivier F1,5, Granger B7, Barrault C8,6, Declèves X1,2.

Abstract
Baclofen has been proposed for few years to help treating alcohol-dependence at higher doses than those used in neurology. Baclofen pharmacokinetics has been previously well described at low oral or intravenous doses but remains poorly investigated with such high oral doses. We here describe dose regimens of baclofen in 143 alcohol-dependent-patients treated with steady-state oral doses of baclofen. Plasma baclofen levels were measured in blood samples using liquid chromatography coupled with tandem mass spectrometry. One-hundred and forty-nine baclofen concentrations were sampled 30 min to 15 h after the last dose and baclofen pharmacokinetics was determined using population pharmacokinetics approach. Our population, whose average age and BMI were 51.5 years and 25.5 kg/m2 , respectively, was composed of two thirds of men. Daily baclofen doses ranged from 15 to 250 mg and 26% were higher than 120 mg. A one-compartment model with first order absorption and elimination allowed to determine mean values for clearance (CL/F), volume of distribution (V/F), and absorption rate constant at 8.0 L/h, 44.5 L and 2.23 h-1 , respectively. Inter-individual variability on CL/F and V/F was 27.4 and 86% for the parameters. None of the demographic and biological covariates significantly decreased inter-individual variability. A proportional relationship between oral dose and plasma baclofen exposure indicated a linear pharmacokinetics of baclofen even at doses over 120 mg per day. Our large population study evidenced a linear pharmacokinetics of oral baclofen even at high daily doses with an inter-individual variability of baclofen exposure that could not be explained by demographic and biological data. This article is protected by copyright. All rights reserved.