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

Nicolas Simon, Nicolas Franchitto, Benjamin Rolland, Nicolas Simon, Nicolas Franchitto, Benjamin Rolland

Abstract

Several clinical randomized trials have evaluated the interest of baclofen in patients with alcohol use disorder. Depending on the study design and the inclusion criteria, the results vary from enthusiastic to pessimistic. However, all researchers and practitioners agree that they observe a wide variability in the therapeutic responses. If some patients exhibit a clinical response at low doses, ~40 mg daily, others require doses higher than 300 mg. Before multiplying new other clinical trials, it is required to better understand the reason of this variability. Several mechanisms may be responsible for providing different effects with an identical daily dose. Especially, each pharmacokinetic step, absorption, distribution, metabolism, and elimination may lead to a different exposure after an identical dose. Absorption may imply a saturation process limiting the bioavailability (F) of baclofen in some patients. In such a situation, food, or drug-drug interaction can change the absorption rate of the drug modifying the maximum concentration (Cmax) and area under the curve (AUC). Distribution and brain penetration across the blood-brain barrier may depend of a specific transporter. These transporters are subject to genetic polymorphism and drug-drug interaction. Finally, elimination may be increased by a specific secretion pathway. This review describes all available pharmacokinetic data on these different pharmacokinetics steps aiming to identify the source of variability of baclofen in patients with alcohol use disorder.

Keywords: GABA; alcohol use disorder; baclofen; clinical pharmacokinetics; modeling.

Figures

Figure 1
Figure 1
Oral dose vs. trough CSF baclofen concentration in patient with severe spasticity. [From data published by Heetla et al. (1) and individuals CSF trough concentration values kindly communicated by the authors].
Figure 2
Figure 2
Simulated concentration vs. time profile following an oral dose of 80 mg of baclofen in four groups of patients with different chronic kidney disease stages.

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