title: 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: Seaside Therapeutics, Inc., 840 Memorial Drive, Cambridge, MA 02139, USA. rsanchez@seasidetherapeutics.com.
authors: Raymundo
authors: R
authors: Sanchez-Ponce
authors: XenoBiotic Laboratories, Inc., 107 Morgan Lane, Plainsboro, NJ 08536, USA. LiQuan_Wang@xbl.com.
authors: Li-Quan
authors: LQ
authors: Wang
authors: XenoBiotic Laboratories, Inc., 107 Morgan Lane, Plainsboro, NJ 08536, USA. wei_lu@xbl.com.
authors: Wei
authors: W
authors: Lu
authors: Seaside Therapeutics, Inc., 840 Memorial Drive, Cambridge, MA 02139, USA. jvonhehn@seasidetherapeutics.com.
authors: Jana
authors: J
authors: von Hehn
authors: Seaside Therapeutics, Inc., 840 Memorial Drive, Cambridge, MA 02139, USA. mcherubini@seasidetherapeutics.com.
authors: Maryann
authors: M
authors: Cherubini
authors: Seaside Therapeutics, Inc., 840 Memorial Drive, Cambridge, MA 02139, USA. rrush@seasidetherapeutics.com.
authors: Roger
authors: R
authors: Rush