Metabolic and Pharmacokinetic Differentiation of STX209 and Racemic Baclofen in Humans.

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.

• Authors: Raymundo Sanchez-Ponce, Li-Quan Wang, Wei Lu, Jana von Hehn, Maryann Cherubini, Roger Rush
• Journal: Metabolites (Metabolites) Vol. 2 Issue 3 Pg. 596-613 (Sep 11 2012) ISSN: 2218-1989 [Print] Switzerland
• PMID: 24957649 (Publication Type: Journal Article)