Full-Profile Pharmacokinetic Study of High Dose Baclofen in Subjects With Alcohol Use Disorder

Simon, Nicolas; Moirand, Romain; Demattéis, Maurice; Bordet, Régis; Deplanque, Dominique; Rolland, Benjamin

doi:10.3389/fpsyt.2018.00385

Cited by 8 publications

(4 citation statements)

References 37 publications

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“…In response to side effects, baclofen administration was suspended or reduced. Because of its short half-life [2–6 h; 93], baclofen was administered in two, three, or four daily administrations.…”

Section: Benefits and Challenges Of The Two Different Approaches Usedmentioning

confidence: 99%

The Use of Baclofen as a Treatment for Alcohol Use Disorder: A Clinical Practice Perspective

et al. 2019

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Alcohol use disorder (AUD) is a brain disorder associated with high rates of mortality and morbidity worldwide. Baclofen, a selective gamma-aminobutyric acid-B (GABA-B) receptor agonist, has emerged as a promising drug for AUD. The use of this drug remains controversial, in part due to uncertainty regarding dosing and efficacy, alongside concerns about safety. To date there have been 15 randomized controlled trials (RCTs) investigating the use of baclofen in AUD; three using doses over 100 mg/day. Two additional RCTs have been completed but have not yet been published. Most trials used fixed dosing of 30–80 mg/day. The other approach involved titration until the desired clinical effect was achieved, or unwanted effects emerged. The maintenance dose varies widely from 30 to more than 300 mg/day. Baclofen may be particularly advantageous in those with liver disease, due to its limited hepatic metabolism and safe profile in this population. Patients should be informed that the use of baclofen for AUD is as an “off-label” prescription, that no optimal fixed dose has been established, and that existing clinical evidence on efficacy is inconsistent. Baclofen therapy requires careful medical monitoring due to safety considerations, particularly at higher doses and in those with comorbid physical and/or psychiatric conditions. Baclofen is mostly used in some European countries and Australia, and in particular, for patients who have not benefitted from the currently used and approved medications for AUD.

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Section: Benefits and Challenges Of The Two Different Approaches Usedmentioning

confidence: 99%

The Use of Baclofen as a Treatment for Alcohol Use Disorder: A Clinical Practice Perspective

et al. 2019

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“…In addition, pharmacokinetic-behavior analyses showed that maximum plasma concentration (Cmax) of baclofen negatively correlated with cue-induced alcohol craving and alcohol-induced rating of 'like more' [24]. Pharmacokinetic analyses in AUD individuals consistently show significant interindividual variability in baclofen pharmacokinetic parameters [23][24][25][26][27], which may be partially responsible for the heterogeneity of response to baclofen.…”

Section: Medications Acting On Gaba Receptors: Baclofenmentioning

confidence: 99%

Prospects for pharmacotherapies to treat alcohol use disorder

Farokhnia

Browning

Leggio

2019

Current Opinion in Psychiatry

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Purpose of review: To provide an update on medication development efforts for alcohol use disorder (AUD) by reviewing recently published (past two years) human studies that evaluated medications' effects on alcohol-related outcomes. Recent findings: Forty-five publications were found suitable for this review. A variety of compounds have been tested in the past two years as potential pharmacological options for AUD, including medications that act on multiple targets (topiramate, aripiprazole, quetiapine), calcium channels (gabapentin), GABA receptors (baclofen, diazepam), glutamate receptors (ifenprodil, memantine, glycine), nicotinic acetylcholine receptors (varenicline, mecamylamine), α1 adrenergic receptors (prazosin, doxazosin), neuroendocrine pathways (oxytocin, a vasopressin receptor 1b antagonist, a ghrelin receptor inverse agonist), and others (samidorphan, ibudilast, Nacetylcysteine, citoline). Important findings and limitations regarding the effects of these medications on alcohol-related outcomes are discussed. Summary: There is a critical need to increase the armamentarium of medications for AUD. Human laboratory studies may help screen and prioritize promising targets and compounds before running large clinical trials. Given the complexity of AUD and the heterogeneity of afflicted patients, future studies should also investigate potential moderators and predictors of response to each pharmacological intervention.

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“…See de Beaurepaire et al (2019), for a review of the use of Baclofen as a treatment in human AUD. Although in recent years, Baclofen has been used to reduce craving, voluntary alcohol intake and withdrawal syndrome of alcoholic patients, a wide inter-individual variability has been observed, and the potential high risk of sedation is unknown (Imbert et al 2015, Simon et al 2018. Thus, the precise efficacy of dosing and the ideal duration of treatment in different AUD patient groups need to be evaluated.…”

Section: Introductionmentioning

confidence: 99%

Hierarchical Bayesian pharmacometrics analysis of Baclofen for alcohol use disorder

Baldy,

Simon,

Jirsa

et al. 2023

Mach. Learn.: Sci. Technol.

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Alcohol use disorder (AUD), also called alcohol dependence, is a major public health problem, affecting almost 10 % of the world’s population. Baclofen, as a selective G A B A B receptor agonist, has emerged as a promising drug for the treatment of AUD. However, the inter-trial, inter-individual and residual variability in drug concentration over time in a population of patients with AUD is unknown. In this study, we use a hierarchical Bayesian workflow to estimate the parameters of a pharmacokinetic (PK) population model from Baclofen administration to patients with AUD. By monitoring various convergence diagnostics, the probabilistic methodology is first validated on synthetic longitudinal datasets and then applied to infer the PK model parameters based on the clinical data that were retrospectively collected from outpatients treated with oral Baclofen. We show that state-of-the-art advances in automatic Bayesian inference using self-tuning Hamiltonian Monte Carlo (HMC) algorithms provide accurate and decisive predictions on Baclofen plasma concentration at both individual and group levels. Importantly, leveraging the information in prior provides faster computation, better convergence diagnostics, and substantially higher out-of-sample prediction accuracy. Moreover, the root mean squared error as a measure of within-sample predictive accuracy can be misleading for model evaluation, whereas the fully Bayesian information criteria correctly select the true data generating parameters. This study points out the capability of non-parametric Bayesian estimation using adaptive HMC sampling methods for easy and reliable estimation in clinical settings to optimize dosing regimens and efficiently treat AUD.

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Full-Profile Pharmacokinetic Study of High Dose Baclofen in Subjects With Alcohol Use Disorder

Cited by 8 publications

References 37 publications

The Use of Baclofen as a Treatment for Alcohol Use Disorder: A Clinical Practice Perspective

The Use of Baclofen as a Treatment for Alcohol Use Disorder: A Clinical Practice Perspective

Prospects for pharmacotherapies to treat alcohol use disorder

Hierarchical Bayesian pharmacometrics analysis of Baclofen for alcohol use disorder

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