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

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/m , 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 , 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/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.

Pharmacokinetic Studies of Baclofen Are Not Sufficient to Establish an Optimized Dosage for Management of Alcohol Disorder

“…Currently only three population pharmacokinetic studies of baclofen have been performed in AUD patients ( 3 , 14 , 31 ). Two studies were based on the same cohort with different objective and population size ( 3 , 31 ).…”

“…The population were AUD patients, mainly male (43 males, 24 females) from 29 to 68-year-old, with a body weight ranging from 42 to 128 kg, normal renal function and a daily baclofen dose up to 180 mg ( 3 ). The second evaluated population present identical demographic and laboratory characteristics ( 14 ). These population pharmacokinetic analysis identified a one-compartment model with first-order input and output to describe the time course of plasma concentrations.…”

“…The baclofen half-life (T1/2) in alcohol-dependent patients with the current immediate release formulation ranged from 3.8 h ( 14 ) to 6.4 h ( 3 ). These values were obtained for doses up to 180 mg per day ( 3 ).…”

“…The Figure 2 depicts these baclofen simulated concentrations following an oral dose of 80 mg in patients according to different values of creatinine clearance. Meanwhile none of the pharmacokinetic studies performed in AUD patients identified a significant influence of creatinine clearance on baclofen clearance ( 3 , 14 , 31 ). This surprising result can be explained by the homogeneity of patients included in these studies regarding the renal function.…”

“…Meanwhile a formula (Equation 1) can be used for computing Tmax from the constant of absorption (Ka) and the constant of elimination (Ke). The calculated Tmax obtained from two population pharmacokinetics studies are 1.23 h ( 14 ) and 1.74 h ( 3 ).…”