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Clinical Trial
. 2018 Apr;43(2):239-249.
doi: 10.1007/s13318-017-0440-z.

Safety, Tolerability and Pharmacokinetics of Oral BI 425809, a Glycine Transporter 1 Inhibitor, in Healthy Male Volunteers: A Partially Randomised, Single-Blind, Placebo-Controlled, First-in-Human Study

Viktoria Moschetti  1 , Michael Desch  2 , Sophia Goetz  2 , Karl-Heinz Liesenfeld  2 , Holger Rosenbrock  2 , Klaus-Peter Kammerer  3 , Glen Wunderlich  4 , Sven Wind  2
Affiliations
Clinical Trial

Safety, Tolerability and Pharmacokinetics of Oral BI 425809, a Glycine Transporter 1 Inhibitor, in Healthy Male Volunteers: A Partially Randomised, Single-Blind, Placebo-Controlled, First-in-Human Study

Viktoria Moschetti et al. Eur J Drug Metab Pharmacokinet. 2018 Apr.

Abstract

Background and objectives: Schizophrenia and Alzheimer's disease are characterised by glutamatergic pathway abnormalities related to N-methyl-D-aspartate (NMDA) receptor hypofunction and cognitive impairment. Glycine is an NMDA receptor co-agonist; inhibition of glycine transporter 1 (GlyT1) should improve NMDA receptor hypofunction. This study evaluated safety and pharmacokinetic properties of BI 425809-a potent and selective GlyT1 inhibitor.

Methods: In the single-rising dose (SRD) component of this study, subjects were randomised to a single dose of BI 425809 [doses (mg): 0.5, 1, 2, 5, 10, 25, 50, 100 and 150], or placebo. The bioavailability/food effect (BA/FE) component investigated BI 425809 pharmacokinetics following single dosing (25-mg tablet) after overnight fasting or with a high-calorie meal or as solution (25 mg) after overnight fasting.

Results: Overall, 33/83 (39.8%) subjects had ≥ 1 treatment-related adverse event (AE); there were no deaths or serious AEs. Reported SRD part AEs trended towards dose dependency, occurring at the higher doses (mostly central nervous system related). BI 425809 plasma concentration-time profiles were similarly shaped across all doses and plasma exposure increased proportional to dose. In the BA/FE component, geometric mean ratios for the area under the concentration-time curve from time zero to the last measurable concentration and the maximum plasma concentration for tablet fasted versus solution fasted were 80.5 and 50.0%, respectively, and for tablet fed versus fasted were 125.9 and 142.1%, respectively.

Conclusion: BI 425809 was generally well-tolerated at doses expected to be clinically relevant. The AE profile suggested possible GlyT1-inhibiting effects.

Clinical trial identifier: NCT02068690.

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Conflict of interest statement

Funding

The work presented here, including the conduct of the study, data analysis and interpretation, was funded by Boehringer Ingelheim. The sponsor was given the opportunity to review the manuscript for medical and scientific accuracy as well as intellectual property considerations. Editorial support in the form of initial preparation of the outline based on input from all authors, and collation and incorporation of author feedback to develop subsequent drafts, assembling tables and figures, copyediting and referencing was provided by Lisa Auker, PhD, of Fishawack Communications, and was funded by Boehringer Ingelheim.

Conflicts of interest

The authors met the criteria for authorship as recommended by the International Committee of Medical Journal Editors. Viktoria Moschetti, Michael Desch, Sophia Goetz, Karl-Heinz Liesenfeld, Holger Rosenbrock, Klaus-Peter Kammerer, Glen Wunderlich and Sven Wind are employees of Boehringer Ingelheim, but received no direct compensation related to the development of this manuscript.

Ethics approval

All procedures in this study were in accordance with the 1964 Helsinki declaration (and its amendments), and were approved by the Independent Ethics Committee at the Human Pharmacology Centre of Boehringer Ingelheim Pharma GmbH and Co. KG, Ingelheim, Germany. All subjects provided written, informed consent before procedures were performed.

Figures

Fig. 1
Fig. 1
Proposed mechanism of action of GlyT1 inhibition on glutamatergic neurotransmission. AMPA-R α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor, Ca 2+ calcium, GlyT1 glycine transporter 1, NMDA-R N-methyl-d-aspartate receptor Figure adapted from Moschetti et al. [17]
Fig. 2
Fig. 2
Geometric mean plasma BI 425809 concentration over time after a single oral doses of 0.5–150 mg (arithmetic mean concentrations) b a single oral 25-mg dose administered as a tablet in the fasted state, as a tablet in the fed state and as solution in the fasted state (geometric mean concentrations)
See this image and copyright information in PMC

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