Abstract | RATIONALE: OBJECTIVES: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
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Authors | Carsten Hofmann, Flavia Pizzagalli, Christophe Boetsch, Daniela Alberati, Larry Ereshefsky, Stanford Jhee, Alain Patat, Bruno Boutouyrie-Dumont, Meret Martin-Facklam |
Journal | Psychopharmacology
(Psychopharmacology (Berl))
Vol. 233
Issue 13
Pg. 2429-39
(07 2016)
ISSN: 1432-2072 [Electronic] Germany |
PMID | 27178435
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- (4-(3-fluoro-5-trifluoromethylpyridin-2-yl)piperazin-1-yl)(5-methanesulfonyl-2-(2,2,2-trifluoro-1-methylethoxy)phenyl)methanone
- Glycine Plasma Membrane Transport Proteins
- Imidazoles
- Neurotransmitter Uptake Inhibitors
- Piperazines
- RG7118
- Receptors, N-Methyl-D-Aspartate
- Sulfones
- Glycine
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Topics |
- Adult
- Area Under Curve
- Brain
(drug effects)
- Glycine
(cerebrospinal fluid)
- Glycine Plasma Membrane Transport Proteins
(antagonists & inhibitors)
- Healthy Volunteers
- Humans
- Imidazoles
(pharmacokinetics, pharmacology)
- Male
- Neurotransmitter Uptake Inhibitors
(pharmacokinetics, pharmacology)
- Piperazines
(pharmacokinetics, pharmacology)
- Receptors, N-Methyl-D-Aspartate
(drug effects)
- Schizophrenia
(drug therapy)
- Sulfones
(pharmacokinetics, pharmacology)
- Synaptic Transmission
(drug effects)
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