Pharmacokinetic-Interactions of BI 425809, a Novel Glycine Transporter 1 Inhibitor, with Cytochrome P450 and P-Glycoprotein Substrates: Findings from in Vitro Analyses and an Open-Label, Single-Sequence Phase i Study

Desch M, Schlecker C, Hohl K, Liesenfeld KH, Chan T, Müller F, Wunderlich G, Keller S, Ishiguro N, Wind S (2023)

Publication Type: Journal article

Publication year: 2023

Journal

Journal of Clinical Psychopharmacology Lippincott, Williams & Wilkins

Book Volume: 43

Pages Range: 113-121

Journal Issue: 2

DOI: 10.1097/JCP.0000000000001656

Abstract

Purpose/Background Glycine transporter-1 inhibitors may ameliorate cognitive deficits in schizophrenia. This study evaluated potential drug-drug interactions with the glycine transporter-1 inhibitor BI 425809. Methods/Procedures Interactions with cytochromes P450 (CYP) and P-glycoprotein (P-gp) were assessed in in vitro assays using human hepatocytes and Caco-2 cells, respectively. Pharmacokinetic characteristics of probe drugs were subsequently assessed in a Phase I, open-label, single-sequence crossover study in healthy male participants. Participants received a probe-drug cocktail containing midazolam (CYP3A4), warfarin (CYP2C9), and omeprazole (CYP2C19) and a separate dose of digoxin (P-gp), alone and on a background of steady-state BI 425809 25 mg once daily in 2 treatment periods. Adverse events were monitored. Findings/Results In vitro assays revealed concentration-dependent induction of CYP3A4 and inhibition of P-gp by BI 425809. In the clinical study, 12 of 13 participants completed both periods. With BI 425809, area under the plasma concentration curve from administration to the last measurement (AUC_0-tz) and maximum plasma concentration (C_max) for midazolam were lower than when administered alone. Adjusted geometric mean ratios (90% confidence interval) were 70.6% (63.9%-78.1%) for AUC_0-tz and 77.6% (67.3%-89.4%) for C_max. For warfarin and digoxin, AUC_0-tz and C_max were similar with and without BI 425809. For omeprazole, BI 425809 slightly reduced AUC_0-tz but not C_max versus omeprazole alone. No new safety signals were identified. Implications/Conclusions These findings indicate induction of CYP3A4 by once-daily BI 425809 25 mg (the assumed highest therapeutic dose) and no meaningful effects on CYP2C9, CYP2C19, or P-gp in vivo.

Involved external institutions

Boehringer Ingelheim Pharma GmbH & Co. KG

Germany (DE) Nippon Boehringer Ingelheim Co Ltd.

Japan (JP)

How to cite

APA:

Desch, M., Schlecker, C., Hohl, K., Liesenfeld, K.H., Chan, T., Müller, F.,... Wind, S. (2023). Pharmacokinetic-Interactions of BI 425809, a Novel Glycine Transporter 1 Inhibitor, with Cytochrome P450 and P-Glycoprotein Substrates: Findings from in Vitro Analyses and an Open-Label, Single-Sequence Phase i Study. Journal of Clinical Psychopharmacology, 43(2), 113-121. https://dx.doi.org/10.1097/JCP.0000000000001656

MLA:

Desch, Michael, et al. "Pharmacokinetic-Interactions of BI 425809, a Novel Glycine Transporter 1 Inhibitor, with Cytochrome P450 and P-Glycoprotein Substrates: Findings from in Vitro Analyses and an Open-Label, Single-Sequence Phase i Study." Journal of Clinical Psychopharmacology 43.2 (2023): 113-121.

BibTeX: Download