PHARMACOKINETICS OF SINGLE AND MULTIPLE RISING DOSES OF BI 425809, A NEW GLYT1 INHIBITOR, IN YOUNG AND ELDERLY HEALTHY VOLUNTEERS

BI 425809, a glycine transporter-1 (GlyT1) inhibitor, is a new chemical entity being developed for the treatment of Alzheimer’s disease. These two trials examined safety, tolerability and characterised pharmacokinetics (PK) after single and multiple doses in young and elderly healthy volunteers (HV). Single rising-dose (SRD): placebo-controlled, single-blind using solution. Within-dose-group randomisation (3:1 drug:placebo) to nine groups (0.5/1/2/5/10/25/50/100/150mg). Bioavailability (BA): randomised, open-label, crossover. 25mg of solution/tablet under fasted/fed conditions. Multiple rising-dose (MRD): 12-day, double-blind, placebo-controlled. Within-dose group randomisation (3:1 drug:placebo) to seven groups (Young HV: 10/25/50/75mg qd; 75mg bid; elderly HV: 25/50mg). SRD: plasma PK profiles similar across dose groups, with rapid absorption and at least biphasic disposition phases. gMean plasma values for Cmax and AUC0-tz of 10.0-2970nmol/L and 115-46,600nmol∙h/L, from 0.5 to 150mg. Linear regression analysis of Cmax, and AUC0-tz provided a slope of ∼1 (dose proportional). Median tmax within 1h for all dose groups; gMean t1/2 from 32.5 to 47.0h. gMean fractional renal excretion consistent and low (∼5%) across all doses. BA: adjusted gMean ratios for Cmax and AUC0-tz for tablet vs solution of 50% (90% CI: 45%-55%), and 81% (74%-88%). Adjusted gMean ratios for Cmax and AUC0-tz∞ for tablet-fed vs tablet-fasted of 142% (128%-157%) and 126% (116%-137%). All AEs non-serious, and mild/moderate intensity, except one severe AE (vomiting) in the highest dose group, with trend towards dose dependency. MRD: tmax ∼4 hours, half-life ∼45 hours, steady state within 8 days. Accumulation ratios of 2.0-2.3× (Cmax) and 2.3-3.0× (AUC) with repeated dosing. Observed trend towards less-than- dose-proportional increase in exposure at doses ≥50 mg. Linearity index ∼1 for doses ≤75 mg qd, decreased at 75 mg bid. No detected PK or safety differences between young/elderly HV. All AEs non-serious and mild/moderate intensity, without dose dependency. BI 425809 PK are compatible with a once-daily dosing regimen, being dose-linear after single administration of 0.5 to 150 mg as solution. Exposure increased less-than-proportionally after administration of doses ≥50 mg as tablets; the compound has a low intrinsic dissolution rate. Exposure was similar in young and elderly HV. BI 425809 was generally well tolerated in all dose groups.