title: Exploratory Biomarker Study of the Triple Reuptake Inhibitor SEP-432 Compared to the Dual Reuptake Inhibitor Duloxetine in Healthy Normal Subjects.
abstract: BACKGROUND
  SEP-432 is a triple monoamine reuptake inhibitor of norepinephrine (NE), serotonin (5-HT), and dopamine (DA), based on in vitro binding studies. We sought evidence that SEP-432 engages these monoamine systems by measuring concentrations of monoamines and/or their main metabolites in cerebrospinal fluid (CSF) and plasma and comparing results to duloxetine, a dual reuptake inhibitor of NE and 5-HT.
  
  
  METHODS
  Eighteen healthy normal subjects received either SEP-432 (300 mg/day), duloxetine (60 mg/day), or placebo for 14 days in-clinic (double blind) with CSF and plasma collections at baseline (single lumbar puncture) and Day 14 (24-h CSF and plasma collection). Concentrations of monoamines and their metabolites, as well as pharmacokinetic concentrations of SEP-432 and metabolite, were quantified by liquid chromatography-tandem mass spectrometry.
  
  
  RESULTS
  Compared to placebo in the Day 14 area under the curve 24-h (AUC0-24 h ) analysis, SEP-432 significantly (P < 0.05) decreased the NE metabolite dihydroxyphenylglycol (DHPG) in CSF and plasma, decreased 5-HT in plasma, and did not affect DA metabolites, while duloxetine had significant effects on DHPG and 5-HT. Time-matched baseline to Day 14 biomarker comparisons confirmed these findings.
  
  
  CONCLUSIONS
  CSF monoamine biomarkers confirmed central NET activity for SEP-432 and duloxetine's dual reuptake inhibition.
authors: Worldwide Clinical Trials, Beverly Hills, CA, USA.
authors: John J
authors: JJ
authors: Sramek
authors: Sunovion Pharmaceuticals, Marlborough, MA, USA.
authors: Larry W
authors: LW
authors: Hardy
authors: Worldwide Clinical Trials, Beverly Hills, CA, USA.
authors: Peter
authors: P
authors: Bieck
authors: Worldwide Clinical Trials, Drug Development Solutions, San Antonio and Austin, TX, USA.
authors: Cynthia
authors: C
authors: Zamora
authors: Sunovion Pharmaceuticals, Marlborough, MA, USA.
authors: Mark
authors: M
authors: Versavel
authors: Sunovion Pharmaceuticals, Marlborough, MA, USA.
authors: Jahnavi
authors: J
authors: Kharidia
authors: Sunovion Pharmaceuticals, Marlborough, MA, USA.
authors: Todd
authors: T
authors: Grinnell
authors: Sunovion Pharmaceuticals, Marlborough, MA, USA.
authors: Yu-Luan
authors: YL
authors: Chen
authors: Worldwide Clinical Trials, Drug Development Solutions, San Antonio and Austin, TX, USA.
authors: Michael
authors: M
authors: Sullivan
authors: Worldwide Clinical Trials, Beverly Hills, CA, USA.
authors: Hong
authors: H
authors: Ding
authors: Worldwide Clinical Trials, Beverly Hills, CA, USA.
authors: Neal R
authors: NR
authors: Cutler
mesh_terms: D000328:Adult; D015306:Biogenic Monoamines / Q000097:blood / Q000134:cerebrospinal fluid; D054316:Biomarkers, Pharmacological / Q000097:blood* / Q000134:cerebrospinal fluid*; D002851:Chromatography, High Pressure Liquid; D003511:Cyclohexanols / Q000494:pharmacology; D004123:Dimethylamines / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D000068736:Duloxetine Hydrochloride / Q000494:pharmacology*; D004562:Electrocardiography; D005260:Female; D064368:Healthy Volunteers; D006801:Humans; D008297:Male; D008734:Methoxyhydroxyphenylglycol / Q000031:analogs & derivatives / Q000378:metabolism; D008875:Middle Aged; D018377:Neurotransmitter Agents / Q000097:blood* / Q000134:cerebrospinal fluid*; D014179:Neurotransmitter Uptake Inhibitors / Q000494:pharmacology*; D053719:Tandem Mass Spectrometry; D013997:Time Factors; D055815:Young Adult
chemical_list: C000613455:4-(3,4-dichlorophenyl)-4-((dimethylamino)methyl)-1-methylcyclohexanol; D015306:Biogenic Monoamines; D054316:Biomarkers, Pharmacological; D003511:Cyclohexanols; D004123:Dimethylamines; D018377:Neurotransmitter Agents; D014179:Neurotransmitter Uptake Inhibitors; D008734:Methoxyhydroxyphenylglycol; D000068736:Duloxetine Hydrochloride; C010117:3,4-dihydroxyphenylglycol
keywords: Biomarkers; Cerebrospinal fluid; Duloxetine; Monoamine reuptake inhibitor; SEP-432