Carsten Hofmann1, Flavia Pizzagalli2,3, Christophe Boetsch2, Daniela Alberati2, Larry Ereshefsky4,5, Stanford Jhee5, Alain Patat6, Bruno Boutouyrie-Dumont2,7, Meret Martin-Facklam2. 1. Roche Pharma Research & Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Grenzacherstr. 124, CH - 4070, Basel, Switzerland. carsten.hofmann@roche.com. 2. Roche Pharma Research & Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Grenzacherstr. 124, CH - 4070, Basel, Switzerland. 3. Daiichi Sankyo Development, Gerrards Cross, UK. 4. University of Texas at Austin, Austin, TX, USA. 5. Parexel International, Los Angeles, CA, USA. 6. Biotrial, Rennes, France. 7. Novartis Institutes for Biomedical Research, Basel, Switzerland.
Abstract
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 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.
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 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.
Authors: D C D'Souza; R Gil; K Cassello; K Morrissey; D Abi-Saab; J White; R Sturwold; A Bennett; L P Karper; E Zuzarte; D S Charney; J H Krystal Journal: Biol Psychiatry Date: 2000-03-01 Impact factor: 13.382
Authors: Daniel Umbricht; Daniela Alberati; Meret Martin-Facklam; Edilio Borroni; Eriene A Youssef; Michael Ostland; Tanya L Wallace; Frédéric Knoflach; Ernest Dorflinger; Joseph G Wettstein; Alexander Bausch; George Garibaldi; Luca Santarelli Journal: JAMA Psychiatry Date: 2014-06 Impact factor: 21.596
Authors: Meret Martin-Facklam; Flavia Pizzagalli; Yun Zhou; Susanne Ostrowitzki; Vanessa Raymont; James R Brašić; Nikhat Parkar; Daniel Umbricht; Robert F Dannals; Ron Goldwater; Dean F Wong Journal: Neuropsychopharmacology Date: 2012-11-07 Impact factor: 7.853
Authors: Amir Mohammadzadeh; Péter P Lakatos; Mihály Balogh; Ferenc Zádor; Dávid Árpád Karádi; Zoltán S Zádori; Kornél Király; Anna Rita Galambos; Szilvia Barsi; Pál Riba; Sándor Benyhe; László Köles; Tamás Tábi; Éva Szökő; Laszlo G Harsing; Mahmoud Al-Khrasani Journal: Int J Mol Sci Date: 2021-03-01 Impact factor: 5.923
Authors: Kevin C F Fone; David J G Watson; Rodolphe I Billiras; Dorothee I Sicard; Anne Dekeyne; Jean-Michel Rivet; Alain Gobert; Mark J Millan Journal: Mol Neurobiol Date: 2020-01-20 Impact factor: 5.590