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Safety and pharmacokinetics of GB1211, an oral galectin-3 inhibitor: a single- and multiple-dose first-in-human study in healthy participants
PURPOSE: Galectin-3, a β-galactoside-binding lectin, plays a key role in several cellular pathways involved in chronic inflammation, heart disease and cancer. GB1211 is an orally bioavailable galectin-3 inhibitor, developed to be systemically active. We report safety and pharmacokinetics (PK) of GB1...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Springer Berlin Heidelberg
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10010643/ https://www.ncbi.nlm.nih.gov/pubmed/36914828 http://dx.doi.org/10.1007/s00280-023-04513-y |
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author | Aslanis, Vassilios Slack, Robert J. MacKinnon, Alison C. McClinton, Catherine Tantawi, Susan Gravelle, Lise Nilsson, Ulf J. Leffler, Hakon Brooks, Ashley Khindri, Sanjeev K. Marshall, Richard P. Pedersen, Anders Schambye, Hans Zetterberg, Fredrik |
author_facet | Aslanis, Vassilios Slack, Robert J. MacKinnon, Alison C. McClinton, Catherine Tantawi, Susan Gravelle, Lise Nilsson, Ulf J. Leffler, Hakon Brooks, Ashley Khindri, Sanjeev K. Marshall, Richard P. Pedersen, Anders Schambye, Hans Zetterberg, Fredrik |
author_sort | Aslanis, Vassilios |
collection | PubMed |
description | PURPOSE: Galectin-3, a β-galactoside-binding lectin, plays a key role in several cellular pathways involved in chronic inflammation, heart disease and cancer. GB1211 is an orally bioavailable galectin-3 inhibitor, developed to be systemically active. We report safety and pharmacokinetics (PK) of GB1211 in healthy participants. METHODS: This phase 1, double-blind, placebo-controlled, first-in-human study (NCT03809052) included a single ascending-dose phase (with a food-effect cohort) where participants across seven sequential cohorts were randomized 3:1 to receive oral GB1211 (5, 20, 50, 100, 200 or 400 mg) or placebo. In the multiple ascending-dose phase, participants received 50 or 100 mg GB1211 or placebo twice daily for 10 days. All doses were administered in the fasted state except in the food-effect cohort where doses were given 30 min after a high-fat meal. RESULTS: All 78 participants received at least one GB1211 dose (n = 58) or placebo (n = 20) and completed the study. No safety concerns were identified. Following single and multiple oral doses under fasted conditions, maximum GB1211 plasma concentrations were reached at 1.75–4 h (median) post-dose; mean half-life was 11–16 h. There was a ~ twofold GB1211 accumulation in plasma with multiple dosing, with steady-state reached within 3 days; 30% of the administered dose was excreted in urine as unchanged drug. Absorption in the fed state was delayed by 2 h but systemic exposure was unaffected. CONCLUSION: GB1211 was well tolerated, rapidly absorbed, and displayed favorable PK, indicating a potential to treat multiple disease types. These findings support further clinical development of GB1211. CLINICAL TRIAL REGISTRATION: The study was registered with ClinicalTrials.gov (identifier: NCT03809052). SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00280-023-04513-y. |
format | Online Article Text |
id | pubmed-10010643 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Springer Berlin Heidelberg |
record_format | MEDLINE/PubMed |
spelling | pubmed-100106432023-03-14 Safety and pharmacokinetics of GB1211, an oral galectin-3 inhibitor: a single- and multiple-dose first-in-human study in healthy participants Aslanis, Vassilios Slack, Robert J. MacKinnon, Alison C. McClinton, Catherine Tantawi, Susan Gravelle, Lise Nilsson, Ulf J. Leffler, Hakon Brooks, Ashley Khindri, Sanjeev K. Marshall, Richard P. Pedersen, Anders Schambye, Hans Zetterberg, Fredrik Cancer Chemother Pharmacol Original Article PURPOSE: Galectin-3, a β-galactoside-binding lectin, plays a key role in several cellular pathways involved in chronic inflammation, heart disease and cancer. GB1211 is an orally bioavailable galectin-3 inhibitor, developed to be systemically active. We report safety and pharmacokinetics (PK) of GB1211 in healthy participants. METHODS: This phase 1, double-blind, placebo-controlled, first-in-human study (NCT03809052) included a single ascending-dose phase (with a food-effect cohort) where participants across seven sequential cohorts were randomized 3:1 to receive oral GB1211 (5, 20, 50, 100, 200 or 400 mg) or placebo. In the multiple ascending-dose phase, participants received 50 or 100 mg GB1211 or placebo twice daily for 10 days. All doses were administered in the fasted state except in the food-effect cohort where doses were given 30 min after a high-fat meal. RESULTS: All 78 participants received at least one GB1211 dose (n = 58) or placebo (n = 20) and completed the study. No safety concerns were identified. Following single and multiple oral doses under fasted conditions, maximum GB1211 plasma concentrations were reached at 1.75–4 h (median) post-dose; mean half-life was 11–16 h. There was a ~ twofold GB1211 accumulation in plasma with multiple dosing, with steady-state reached within 3 days; 30% of the administered dose was excreted in urine as unchanged drug. Absorption in the fed state was delayed by 2 h but systemic exposure was unaffected. CONCLUSION: GB1211 was well tolerated, rapidly absorbed, and displayed favorable PK, indicating a potential to treat multiple disease types. These findings support further clinical development of GB1211. CLINICAL TRIAL REGISTRATION: The study was registered with ClinicalTrials.gov (identifier: NCT03809052). SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00280-023-04513-y. Springer Berlin Heidelberg 2023-03-13 2023 /pmc/articles/PMC10010643/ /pubmed/36914828 http://dx.doi.org/10.1007/s00280-023-04513-y Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Original Article Aslanis, Vassilios Slack, Robert J. MacKinnon, Alison C. McClinton, Catherine Tantawi, Susan Gravelle, Lise Nilsson, Ulf J. Leffler, Hakon Brooks, Ashley Khindri, Sanjeev K. Marshall, Richard P. Pedersen, Anders Schambye, Hans Zetterberg, Fredrik Safety and pharmacokinetics of GB1211, an oral galectin-3 inhibitor: a single- and multiple-dose first-in-human study in healthy participants |
title | Safety and pharmacokinetics of GB1211, an oral galectin-3 inhibitor: a single- and multiple-dose first-in-human study in healthy participants |
title_full | Safety and pharmacokinetics of GB1211, an oral galectin-3 inhibitor: a single- and multiple-dose first-in-human study in healthy participants |
title_fullStr | Safety and pharmacokinetics of GB1211, an oral galectin-3 inhibitor: a single- and multiple-dose first-in-human study in healthy participants |
title_full_unstemmed | Safety and pharmacokinetics of GB1211, an oral galectin-3 inhibitor: a single- and multiple-dose first-in-human study in healthy participants |
title_short | Safety and pharmacokinetics of GB1211, an oral galectin-3 inhibitor: a single- and multiple-dose first-in-human study in healthy participants |
title_sort | safety and pharmacokinetics of gb1211, an oral galectin-3 inhibitor: a single- and multiple-dose first-in-human study in healthy participants |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10010643/ https://www.ncbi.nlm.nih.gov/pubmed/36914828 http://dx.doi.org/10.1007/s00280-023-04513-y |
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