Abstract
STX209 is an exploratory drug comprising the single, active R-enantiomer of baclofen which is in later stage clinical trials for the treatment of fragile x syndrome (FXS) and autism spectrum disorders (ASD). New clinical data in this article on the metabolism and pharmacokinetics of the R- and S-enantiomers of baclofen presents scientific evidence for stereoselective metabolism of only S-baclofen to an abundant oxidative deamination metabolite that is sterically resolved as the S-enantiomeric configuration. This metabolite undergoes some further metabolism by glucuronide conjugation. Consequences of this metabolic difference are a lower Cmax and lower early plasma exposure of S-baclofen compared to R-baclofen and marginally lower urinary excretion of S-baclofen after racemic baclofen administration. These differences introduce compound-related exposure variances in humans in which subjects dosed with racemic baclofen are exposed to a prominent metabolite of baclofen whilst subjects dosed with STX209 are not. For potential clinical use, our findings suggest that STX209 has the advantage of being a biologically defined and active enantiomer.
Highlights
Baclofen (Figure 1), (±)-4-amino-3-(p-chlorophenyl)-butanoic acid, is a racemic drug, comprising equal amounts of the R- and S-enantiomers, approved over thirty years ago for the treatment of spasticity in adults and children as young as 12 years of age (Lioresal®, NDA 017851, USA FDA 1977)
STX209 is an exploratory drug comprising the single, active R-enantiomer of baclofen which is being evaluated by Seaside Therapeutics, Inc. in later stage clinical trials for the treatment of fragile x syndrome (FXS) and autism spectrum disorder (ASD) [1]
In this article we present new clinical data on the metabolism and pharmacokinetics of the two enantiomers of baclofen
Summary
Baclofen (Figure 1), (±)-4-amino-3-(p-chlorophenyl)-butanoic acid, is a racemic drug, comprising equal amounts of the R- and S-enantiomers, approved over thirty years ago for the treatment of spasticity in adults and children as young as 12 years of age (Lioresal®, NDA 017851, USA FDA 1977). STX209 is an exploratory drug comprising the single, active R-enantiomer of baclofen which is being evaluated by Seaside Therapeutics, Inc. in later stage clinical trials for the treatment of fragile x syndrome (FXS) and autism spectrum disorder (ASD) [1]. Information on the clinical disposition of baclofen was first described by Faigle and Keberle in 1972 following a 40 mg single oral dose containing 14C-baclofen. Some 85% of the dose was excreted as unchanged drug with one major metabolite identified as the deamination product, 3-(4-chlorophenyl)-4-hydroxybutyric acid [3]. Metabolites constituted less than 10% of the material excreted in urine
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