Cargando…
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
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) we...
Autores principales: | , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Lippincott Williams & Wilkins
2023
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9988221/ https://www.ncbi.nlm.nih.gov/pubmed/36700734 http://dx.doi.org/10.1097/JCP.0000000000001656 |
_version_ | 1784901532426174464 |
---|---|
author | Desch, Michael Schlecker, Christina Hohl, Kathrin Liesenfeld, Karl-Heinz Chan, Tom Müller, Fabian Wunderlich, Glen Keller, Sascha Ishiguro, Naoki Wind, Sven |
author_facet | Desch, Michael Schlecker, Christina Hohl, Kathrin Liesenfeld, Karl-Heinz Chan, Tom Müller, Fabian Wunderlich, Glen Keller, Sascha Ishiguro, Naoki Wind, Sven |
author_sort | Desch, Michael |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-9988221 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Lippincott Williams & Wilkins |
record_format | MEDLINE/PubMed |
spelling | pubmed-99882212023-03-07 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, Michael Schlecker, Christina Hohl, Kathrin Liesenfeld, Karl-Heinz Chan, Tom Müller, Fabian Wunderlich, Glen Keller, Sascha Ishiguro, Naoki Wind, Sven J Clin Psychopharmacol Original Contributions 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. Lippincott Williams & Wilkins 2023 2023-01-26 /pmc/articles/PMC9988221/ /pubmed/36700734 http://dx.doi.org/10.1097/JCP.0000000000001656 Text en Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND) (https://creativecommons.org/licenses/by-nc-nd/4.0/) , where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. |
spellingShingle | Original Contributions Desch, Michael Schlecker, Christina Hohl, Kathrin Liesenfeld, Karl-Heinz Chan, Tom Müller, Fabian Wunderlich, Glen Keller, Sascha Ishiguro, Naoki Wind, Sven 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 |
title | 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 |
title_full | 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 |
title_fullStr | 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 |
title_full_unstemmed | 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 |
title_short | 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 |
title_sort | 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 |
topic | Original Contributions |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9988221/ https://www.ncbi.nlm.nih.gov/pubmed/36700734 http://dx.doi.org/10.1097/JCP.0000000000001656 |
work_keys_str_mv | AT deschmichael pharmacokineticinteractionsofbi425809anovelglycinetransporter1inhibitorwithcytochromep450andpglycoproteinsubstratesfindingsfrominvitroanalysesandanopenlabelsinglesequencephaseistudy AT schleckerchristina pharmacokineticinteractionsofbi425809anovelglycinetransporter1inhibitorwithcytochromep450andpglycoproteinsubstratesfindingsfrominvitroanalysesandanopenlabelsinglesequencephaseistudy AT hohlkathrin pharmacokineticinteractionsofbi425809anovelglycinetransporter1inhibitorwithcytochromep450andpglycoproteinsubstratesfindingsfrominvitroanalysesandanopenlabelsinglesequencephaseistudy AT liesenfeldkarlheinz pharmacokineticinteractionsofbi425809anovelglycinetransporter1inhibitorwithcytochromep450andpglycoproteinsubstratesfindingsfrominvitroanalysesandanopenlabelsinglesequencephaseistudy AT chantom pharmacokineticinteractionsofbi425809anovelglycinetransporter1inhibitorwithcytochromep450andpglycoproteinsubstratesfindingsfrominvitroanalysesandanopenlabelsinglesequencephaseistudy AT mullerfabian pharmacokineticinteractionsofbi425809anovelglycinetransporter1inhibitorwithcytochromep450andpglycoproteinsubstratesfindingsfrominvitroanalysesandanopenlabelsinglesequencephaseistudy AT wunderlichglen pharmacokineticinteractionsofbi425809anovelglycinetransporter1inhibitorwithcytochromep450andpglycoproteinsubstratesfindingsfrominvitroanalysesandanopenlabelsinglesequencephaseistudy AT kellersascha pharmacokineticinteractionsofbi425809anovelglycinetransporter1inhibitorwithcytochromep450andpglycoproteinsubstratesfindingsfrominvitroanalysesandanopenlabelsinglesequencephaseistudy AT ishiguronaoki pharmacokineticinteractionsofbi425809anovelglycinetransporter1inhibitorwithcytochromep450andpglycoproteinsubstratesfindingsfrominvitroanalysesandanopenlabelsinglesequencephaseistudy AT windsven pharmacokineticinteractionsofbi425809anovelglycinetransporter1inhibitorwithcytochromep450andpglycoproteinsubstratesfindingsfrominvitroanalysesandanopenlabelsinglesequencephaseistudy |