Effects of Cytochrome P450 3A4 Induction and Inhibition on the Pharmacokinetics of BI 425809, a Novel Glycine Transporter 1 Inhibitor.

BACKGROUND AND OBJECTIVE: Increased glycine availability at the synaptic cleft may enhance N-methyl-D-aspartate receptor signalling and provide a promising therapeutic strategy for cognitive impairment associated with schizophrenia. These studies aimed to assess the pharmacokinetics of BI 425809, a potent glycine-transporter-1 inhibitor, when co-administered with a strong cytochrome P450 3A4 (CYP3A4) inhibitor (itraconazole) and inducer (rifampicin). METHODS: In vitro studies using recombinant CYPs, human liver microsomes, and human hepatocytes were conducted to determine the CYP isoforms responsible for BI 425809 metabolism. In addition, two open-label, fixed-treatment period, phase I studies in healthy male volunteers are described. Period 1: participants received oral BI 425809 25 mg (single dose) on day 1; period 2: participants received multiple doses, across 10 days, of oral itraconazole or rifampicin combined with a single dose of oral BI 425809 25 mg on day 4/7 of the itraconazole/rifampicin treatment, respectively. Pharmacokinetic and safety endpoints were assessed in the absence/presence of itraconazole/rifampicin and included area under the concentration-time curve (AUC) over the time interval 0-167 h (AUC0‒167; itraconazole), 0-168 h (AUC0‒168; rifampicin), or 0-infinity (AUC0-∞; rifampicin and itraconazole), maximum measured concentration (Cmax) of BI 425809, and adverse events. RESULTS: In vitro results suggested that CYP3A4 accounted for ≥ 90% of the metabolism of BI 425809. BI 425809 exposure (adjusted geometric mean ratio [%]) was higher in the presence of itraconazole (AUC0‒167: 265.3; AUC0-∞: 597.0; Cmax: 116.1) and lower in the presence of rifampicin (AUC0‒168: 10.3; AUC0-∞: 9.8; Cmax: 37.4) compared with BI 425809 alone. Investigational treatments were well tolerated. CONCLUSIONS: Systemic exposure of BI 425809 was altered in the presence of strong CYP3A4 modulators, corroborating in vitro results that CYP3A4 mediates a major metabolic pathway for BI 425809. TRIAL REGISTRATION NUMBER: NCT02342717 (registered on 15 January 2015) and NCT03082183 (registered on 10 March 2017).

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.

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.

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.

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.

Evaluation of Pharmacokinetics and Pharmacodynamics of BI 425809, a Novel GlyT1 Inhibitor: Translational Studies.

BI 425809 is a potent and selective glycine transporter 1 (GlyT1) inhibitor being developed for the treatment of cognitive impairment in Alzheimer disease and schizophrenia. Translational studies evaluated the effects of BI 425809 on glycine levels in rat and human cerebrospinal fluid (CSF). Oral administration of BI 425809 in rats induced a dose-dependent increase of glycine CSF levels from 30% (0.2 mg/kg, not significant) to 78% (2 mg/kg, P < 0.01), relative to vehicle. Similarly, oral administration of BI 425809 in healthy volunteers resulted in a dose-dependent increase in glycine CSF levels at steady state, with a mean 50% increase at doses as low as 10 mg. The peak plasma concentration (Cmax ) of BI 425809 was achieved earlier in plasma than in CSF (tmax 3-5 vs. 5-8 hours, respectively). Generally, BI 425809 was safe and well tolerated. These data provide evidence of functional target engagement of GlyT1 by BI 425809.