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Metabolites 2012, 2(3), 596-613; doi:10.3390/metabo2030596

Metabolic and Pharmacokinetic Differentiation of STX209 and Racemic Baclofen in Humans

1,* , 2
1 Seaside Therapeutics, Inc., 840 Memorial Drive, Cambridge, MA 02139, USA 2 XenoBiotic Laboratories, Inc., 107 Morgan Lane, Plainsboro, NJ 08536, USA
* Author to whom correspondence should be addressed.
Received: 25 July 2012 / Revised: 21 August 2012 / Accepted: 29 August 2012 / Published: 11 September 2012
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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.
Keywords: pharmacokinetics; baclofen; R-baclofen; metabolic differentiation pharmacokinetics; baclofen; R-baclofen; metabolic differentiation
This is an open access article distributed under the Creative Commons Attribution License (CC BY 3.0).

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Sanchez-Ponce, R.; Wang, L.-Q.; Lu, W.; von Hehn, J.; Cherubini, M.; Rush, R. Metabolic and Pharmacokinetic Differentiation of STX209 and Racemic Baclofen in Humans. Metabolites 2012, 2, 596-613.

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