title: Effects of the glycine reuptake inhibitors bitopertin and RG7118 on glycine in cerebrospinal fluid: results of two proofs of mechanism studies in healthy volunteers.
abstract: Hypofunction of NMDA receptors has been implicated in neuropsychiatric disorders including schizophrenia. NMDA receptor neurotransmission can be enhanced through inhibition of glycine reuptake by the glycine transporter type 1 (GlyT1).
  
  
  
  The primary objective of these studies was to explore the relationship between plasma exposure and glycine cerebrospinal fluid (CSF) concentrations following administration of bitopertin and RG7118 in healthy volunteers.
  
  
  
  The bitopertin study comprised four dose levels (3, 10, 30 and 60 mg) administered once daily for 10 days. In the RG7118 study, placebo, 15 or 30 mg RG7118 was administered once daily for 28 days. CSF samples were taken on day -2 and day 10, and day -1 and day 26 for bitopertin and RG7118, respectively.
  
  
  
  Twenty-two and 24 subjects participated in the bitopertin and RG7118 study, respectively. In the bitopertin study, CSF glycine concentrations showed a dose-dependent increase from baseline to day 10. The geometric mean ratios (coefficient of variation) of AUC0-12 h on day 10 over baseline were 1.3 (17 %), 1.3 (49 %), 1.7 (18 %) and 2.3 (14 %) after 3, 10, 30 and 60 mg, respectively. In the RG7118 study, the geometric mean ratio of glycine concentration (CV) on day 26 at 6 h post-dose over time-matched baseline was approx. 1.9 (24 and 15 %) for 15 and 30 mg.
  
  
  
  The mechanism of action of bitopertin and RG7118, i.e. inhibition of glycine reuptake in the brain, was confirmed. The maximal increase observed in healthy volunteers was similar to the one observed in animals showing the good translatability of this biomarker.
authors.affiliation: Roche Pharma Research & Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Grenzacherstr. 124, CH - 4070, Basel, Switzerland. carsten.hofmann@roche.com.
authors.forename: Carsten
authors.initials: C
authors.lastname: Hofmann
authors.affiliation: Roche Pharma Research & Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Grenzacherstr. 124, CH - 4070, Basel, Switzerland.|Daiichi Sankyo Development, Gerrards Cross, UK.
authors.forename: Flavia
authors.initials: F
authors.lastname: Pizzagalli
authors.affiliation: Roche Pharma Research & Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Grenzacherstr. 124, CH - 4070, Basel, Switzerland.
authors.forename: Christophe
authors.initials: C
authors.lastname: Boetsch
authors.affiliation: Roche Pharma Research & Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Grenzacherstr. 124, CH - 4070, Basel, Switzerland.
authors.forename: Daniela
authors.initials: D
authors.lastname: Alberati
authors.affiliation: University of Texas at Austin, Austin, TX, USA.|Parexel International, Los Angeles, CA, USA.
authors.forename: Larry
authors.initials: L
authors.lastname: Ereshefsky
authors.affiliation: Parexel International, Los Angeles, CA, USA.
authors.forename: Stanford
authors.initials: S
authors.lastname: Jhee
authors.affiliation: Biotrial, Rennes, France.
authors.forename: Alain
authors.initials: A
authors.lastname: Patat
authors.affiliation: Roche Pharma Research & Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Grenzacherstr. 124, CH - 4070, Basel, Switzerland.|Novartis Institutes for Biomedical Research, Basel, Switzerland.
authors.forename: Bruno
authors.initials: B
authors.lastname: Boutouyrie-Dumont
authors.affiliation: Roche Pharma Research & Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Grenzacherstr. 124, CH - 4070, Basel, Switzerland.
authors.forename: Meret
authors.initials: M
authors.lastname: Martin-Facklam
mesh_terms: D000328:Adult; D019540:Area Under Curve; D001921:Brain / Q000187:drug effects; D005998:Glycine / Q000134:cerebrospinal fluid*; D050487:Glycine Plasma Membrane Transport Proteins / Q000037:antagonists & inhibitors*; D064368:Healthy Volunteers; D006801:Humans; D007093:Imidazoles / Q000493:pharmacokinetics / Q000494:pharmacology*; D008297:Male; D014179:Neurotransmitter Uptake Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D010879:Piperazines / Q000493:pharmacokinetics / Q000494:pharmacology*; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects; D012559:Schizophrenia / Q000188:drug therapy; D013450:Sulfones / Q000493:pharmacokinetics / Q000494:pharmacology*; D009435:Synaptic Transmission / Q000187:drug effects*
chemical_list: C550631:(4-(3-fluoro-5-trifluoromethylpyridin-2-yl)piperazin-1-yl)(5-methanesulfonyl-2-(2,2,2-trifluoro-1-methylethoxy)phenyl)methanone; D050487:Glycine Plasma Membrane Transport Proteins; D007093:Imidazoles; D014179:Neurotransmitter Uptake Inhibitors; D010879:Piperazines; C000625156:RG7118; D016194:Receptors, N-Methyl-D-Aspartate; D013450:Sulfones; D005998:Glycine
keywords: Bitopertin; Cerebrospinal fluid; GLYT1; Glycine transporter 1 inhibitor; Pharmacodynamics; SLC6A9; Schizophrenia