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

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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.

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Acknowledgments

The authors would like to thank the following contributors: Ludger Banken for his guidance on statistical aspects of the clinical studies and Stephane Frecinaux and Caroline Cajot from Quality-Assistance in Donstiennes, Belgium, for their valuable input in study design and the analysis of the glycine concentration in CSF and Plasma, AAIPharma Deutschland GmbH & Co. KG Bioanalytics, Neu-Ulm, Germany.

Author contributions

Participated in research design: Hofmann, Pizzagalli, Boetsch, Alberati, Boutouyrie-Dumont and Martin-Facklam

Conducted experiments: Ereshefsky, Jhee and Patat

Performed data analysis: Hofmann, Pizzagalli, Boetsch and Martin-Facklam

Wrote or contributed to writing the manuscript: Martin-Facklam and Hofmann

Reviewed manuscript drafts and approved final version for submission: Hofmann, Pizzagalli, Boetsch, Alberati, Ereshefsky, Jhee, Boutouyrie-Dumont and Martin-Facklam

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Authors and Affiliations

  1. Roche Pharma Research & Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Grenzacherstr. 124, CH - 4070, Basel, Switzerland

    Carsten Hofmann, Flavia Pizzagalli, Christophe Boetsch, Daniela Alberati, Bruno Boutouyrie-Dumont & Meret Martin-Facklam

  2. Daiichi Sankyo Development, Gerrards Cross, UK

    Flavia Pizzagalli

  3. University of Texas at Austin, Austin, TX, USA

    Larry Ereshefsky

  4. Parexel International, Los Angeles, CA, USA

    Larry Ereshefsky & Stanford Jhee

  5. Biotrial, Rennes, France

    Alain Patat

  6. Novartis Institutes for Biomedical Research, Basel, Switzerland

    Bruno Boutouyrie-Dumont

Authors
  1. Carsten Hofmann
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  2. Flavia Pizzagalli
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  3. Christophe Boetsch
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  4. Daniela Alberati
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  5. Larry Ereshefsky
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  6. Stanford Jhee
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  7. Alain Patat
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  8. Bruno Boutouyrie-Dumont
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  9. Meret Martin-Facklam
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Corresponding author

Correspondence to Carsten Hofmann.

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Conflict of interest

CH, FP, CB, DA, BBD and MMF were employees of F. Hoffmann-La Roche when this work was carried out.

Funding

Parexel International (LE, SJ) received funding from F. Hoffmann-La Roche to perform the bitopertin study. Biotrial (AP) received funding from F. Hoffmann-La Roche to perform RG7118 study.

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Hofmann, C., Pizzagalli, F., Boetsch, C. et al. Effects of the glycine reuptake inhibitors bitopertin and RG7118 on glycine in cerebrospinal fluid: results of two proofs of mechanism studies in healthy volunteers. Psychopharmacology 233, 2429–2439 (2016). https://doi.org/10.1007/s00213-016-4317-7

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  • DOI: https://doi.org/10.1007/s00213-016-4317-7

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