title: Chiral liquid chromatography-tandem mass spectrometry assay to determine that dexpramipexole is not converted to pramipexole in vivo after administered in humans.
abstract: Dexpramipexole (DEX) was being investigated in clinical studies for the treatment of amyotrophic lateral sclerosis (ALS). To monitor the potential chiral interconversion of dexpramipexole to pramipexole (PPX) in vivo, a highly sensitive and selective chiral LC-MS/MS assay was developed and qualified for the detection of pramipexole in the presence of dexpramipexole in human plasma. In this assay, plasma samples were extracted by protein precipitation coupled with solid phase extraction (SPE). The analyte PPX was separated from its enantiomer DEX using a chiral HPLC method. The assay was qualified with a dynamic range of 0.150-1.00ng/mL. The lower limit of quantitation (LLOQ) for PPX was 0.150ng/mL in the presence of up to 1000ng/mL of DEX. The qualified method was used to analyze plasma samples from a DEX clinical study. No PPX was detected in humans at pharmacologically significant levels after administration of dexpramipexole at single doses up to 600mg per day.
authors.affiliation: Biogen Idec, Inc., 14 Cambridge Center, Cambridge, MA 02142, USA. Electronic address: dong.wei@biogenidec.com.
authors.forename: Dong
authors.initials: D
authors.lastname: Wei
authors.affiliation: Biogen Idec, Inc., 14 Cambridge Center, Cambridge, MA 02142, USA.
authors.forename: Chichih
authors.initials: C
authors.lastname: Wu
authors.affiliation: Pfizer, Inc., 610 Main Street, Cambridge, MA 02139, USA.
authors.forename: Ping
authors.initials: P
authors.lastname: He
authors.affiliation: Biogen Idec, Inc., 14 Cambridge Center, Cambridge, MA 02142, USA.
authors.forename: Doug
authors.initials: D
authors.lastname: Kerr
authors.affiliation: Biogen Idec, Inc., 14 Cambridge Center, Cambridge, MA 02142, USA.
authors.forename: Scott
authors.initials: S
authors.lastname: Stecher
authors.affiliation: Biogen Idec, Inc., 14 Cambridge Center, Cambridge, MA 02142, USA.
authors.forename: Liyu
authors.initials: L
authors.lastname: Yang
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000188:drug therapy; D052160:Benzothiazoles / Q000008:administration & dosage* / Q000097:blood* / Q000737:chemistry / Q000493:pharmacokinetics; D002853:Chromatography, Liquid / Q000379:methods*; D004355:Drug Stability; D006801:Humans; D010919:Placebos; D000077487:Pramipexole; D011786:Quality Control; D012680:Sensitivity and Specificity; D013237:Stereoisomerism; D053719:Tandem Mass Spectrometry / Q000379:methods*
chemical_list: D052160:Benzothiazoles; D010919:Placebos; D000077487:Pramipexole
keywords: Bioanalysis; Chiral HPLC; Chiral interconversion; Dexpramipexole; LC–MS/MS