Multiple Rising Doses of Oral BI 425809, a GlyT1 Inhibitor, in Young and Elderly Healthy Volunteers: A Randomised, Double-Blind, Phase I Study Investigating Safety and Pharmacokinetics

Abstract

Background and objective: Schizophrenia and Alzheimer's disease are characterised by abnormalities in glutamatergic pathways related to N-methyl-D-aspartate receptor hypofunction. Glycine is an N-methyl-D-aspartate receptor co-agonist; inhibition of glycine transporter 1 may improve N-methyl-D-aspartate receptor function. This phase I, randomised, two-part study evaluated the safety, tolerability and pharmacokinetic profile of BI 425809, a novel glycine transporter 1 inhibitor, in healthy male and female volunteers.

Methods: Part 1 evaluated BI 425809 10, 25, 50 or 75 mg once daily or 75 mg twice daily in young subjects, and 25 mg or 50 mg once daily in elderly subjects. Each dose group comprised 12 subjects who received BI 425809 (n = 9) or placebo (n = 3) for 14 days (day 1: single dose; days 4-14: multiple dosing). Part 2 compared pharmacokinetic profiles in 12 subjects who received a single dose of BI 425809 25 mg in the morning and evening.

Results: Pharmacokinetic profiles were similarly shaped for all dose groups. Median time to maximum plasma concentration was 3.0-4.5 h with steady state being reached between days 6 and 10. Pharmacokinetic parameters demonstrated dose linearity at the predicted therapeutic exposure range of BI 425809 ≤ 25 mg once daily, but increased less than dose proportionally for ≥ 50 mg once daily. All reported adverse events were of mild-to-moderate intensity, 51/84 (61%; part 1) subjects had one or more treatment-related adverse event, no serious adverse events occurred and no dose dependency was observed.

Conclusions: Pharmacokinetic properties support both morning and evening dosing. BI 425809 was generally well tolerated at all tested doses. CLINICALTRIALS.

Gov identifier: NCT02337283.

Conflict of interest statement

Conflict of interest

The authors met the criteria for authorship as recommended by the International Committee of Medical Journal Editors. All authors (except Armin Schultz, who is an employee of CRS Clinical Research Services, Mannheim) are employees of Boehringer Ingelheim, but received no direct compensation related to the development of this manuscript. Armin Schultz has no disclosures to declare.

Ethics approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

Consent to participate

Informed consent was obtained from all individual participants included in the study.

Figures

Fig. 1

Study design diagram. BID twice daily, HE healthy elderly, HY healthy young, PK pharmacokinetics, QD once daily

Fig. 2

CONSORT diagram. AE adverse event, HE healthy elderly, HY healthy young, PK pharmacokinetics, PKS all subjects from the Treated set who received BI 425809, participated in part 1, and provided one or more PK endpoints judged as evaluable, Treated set all subjects who received at least one dose of study drug/placebo

Fig. 3

Geometric mean drug plasma concentration–time profiles of BI 425809 after single and multiple oral administration of BI 425809 tablets: a once daily (QD) or twice daily (BID) in young and elderly subjects and b QD in young vs. elderly subjects (semi-log scale)

Fig. 4

Intra-individual comparison of a area under the concentration–time curve over the time interval from 0 to the last quantifiable data point (AUC0–tz) and b maximum plasma concentration (Cmax) values of BI 425809 after single oral administration of 25 mg in the morning or in the evening in healthy young subjects. gMean geometric mean, QD once daily