Effects of the glycine reuptake inhibitors bitopertin and RG7118 on glycine in cerebrospinal fluid: results of two proofs of mechanism studies in healthy volunteers

• Published in: Psychopharmacology Vol. 233; no. 13; pp. 2429 - 2439
• Main Authors: Hofmann, Carsten, Pizzagalli, Flavia, Boetsch, Christophe, Alberati, Daniela, Ereshefsky, Larry, Jhee, Stanford, Patat, Alain, Boutouyrie-Dumont, Bruno, Martin-Facklam, Meret
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Science and Business Media LLC 01.07.2016; Springer Berlin Heidelberg; Springer; Springer Nature B.V
• Subjects: Adult; Area Under Curve; Biomedical and Life Sciences; Biomedicine; Brain; Brain - drug effects; Cerebrospinal fluid; Chemical inhibitors; Dosage and administration; Glycine; Glycine - cerebrospinal fluid; Glycine Plasma Membrane Transport Proteins; Glycine Plasma Membrane Transport Proteins - antagonists & inhibitors; Health aspects; Healthy Volunteers; Humans; Imidazoles; Imidazoles - pharmacokinetics; Imidazoles - pharmacology; Male; Neurons; Neurosciences; Neurotransmitter Uptake Inhibitors; Neurotransmitter Uptake Inhibitors - pharmacokinetics; Neurotransmitter Uptake Inhibitors - pharmacology; Original Investigation; Patient outcomes; Pharmacology; Pharmacology/Toxicology; Piperazines; Piperazines - pharmacokinetics; Piperazines - pharmacology; Psychiatry; Receptors, N-Methyl-D-Aspartate; Receptors, N-Methyl-D-Aspartate - drug effects; Schizophrenia; Schizophrenia - drug therapy; Studies; Sulfones; Sulfones - pharmacokinetics; Sulfones - pharmacology; Synaptic Transmission; Synaptic Transmission - drug effects; Volunteers; Pharmacodynamics; SLC6A9; Schizophrenia; Cerebrospinal fluid; Glycine transporter 1 inhibitor; GLYT1; Bitopertin
• ISSN: 0033-3158; 1432-2072; 1432-2072
• DOI: 10.1007/s00213-016-4317-7

Rationale 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). 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 AUC 0–12 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.