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
Bibliographic record
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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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.003 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".