Safety, Tolerability and Pharmacokinetics of an NMDA Receptor Subunit 2B-Selective Negative Allosteric Modulator, BI 1569912: Results of Three Partially Randomised, Placebo-Controlled Phase I Trials.

BACKGROUND:BI 1569912 is an orally administered, GluN2B-selective negative allosteric modulator at the N-methyl-D-aspartate receptor. AIMS:To investigate the safety, tolerability and pharmacokinetics (PK) of BI 1569912 in healthy males across three partially randomised, placebo-controlled, parallel-group phase I trials. METHODS:Trial 1 evaluated single rising doses (SRD) of BI 1569912 versus placebo in Germany and assessed formulation and food effects on bioavailability. Trial 2 evaluated multiple rising doses (MRD) of BI 1569912 versus placebo in young and elderly participants in Germany. Trial 3 investigated single rising and multiple doses (MD) of BI 1569912 in participants in Japan, including PK to assess morning versus evening dosing. RESULTS:Trial completion/randomisation numbers were: Trial 1 (SRD part, 54/55; bioavailability/food effect part, 8/13); Trial 2 (MRD part, 71/71; Elderly part, 12/12); Trial 3 (SRD part, 32/32; MD part, 12/12; evening PK part, 12/12). No deaths, serious adverse events (AEs), AEs of special interest, or discontinuations because of AEs were reported. There was no clinical evidence clearly suggestive of dissociation. After oral administration, BI 1569912 was rapidly absorbed and eliminated, with dose-proportional increases in plasma exposure. Formulation (oral solution vs tablet) did not affect PK. Administration with food reduced Cmax and delayed Tmax without affecting AUC; likewise, evening dosing lowered Cmax versus morning while AUC remained similar. Steady state was achieved by Day 3 of multiple dosing. Exposure was similar between young and elderly participants. Urinary excretion of unchanged drug was negligible. CONCLUSIONS:BI 1569912 demonstrated favourable safety and PK profiles in healthy participants.Clinical trial registration: Trial 1 (ClinicalTrials.gov: NCT04445090 (1447-0001)); Trial 2 (ClinicalTrials.gov: NCT04978506 (1447-0002)); Trial 3 (ClinicalTrials.gov: NCT04958252 (1447-0004)).