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Pharmacokinetics and Safety of Glasdegib in Participants With Moderate/Severe Hepatic Impairment: A Phase I, Single‐Dose, Matched Case‐Control Study
This phase I open‐label trial (NCT03627754) assessed glasdegib pharmacokinetics and safety in otherwise healthy participants with moderate (Child‐Pugh B) or severe (Child‐Pugh C) hepatic impairment. Participants with hepatic impairment and age/weight‐matched controls with normal hepatic function rec...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8359308/ https://www.ncbi.nlm.nih.gov/pubmed/33356019 http://dx.doi.org/10.1002/cpdd.897 |
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author | Masters, Joanna C. LaBadie, Robert R. Salageanu, Joanne Li, Jerry Shaik, Naveed |
author_facet | Masters, Joanna C. LaBadie, Robert R. Salageanu, Joanne Li, Jerry Shaik, Naveed |
author_sort | Masters, Joanna C. |
collection | PubMed |
description | This phase I open‐label trial (NCT03627754) assessed glasdegib pharmacokinetics and safety in otherwise healthy participants with moderate (Child‐Pugh B) or severe (Child‐Pugh C) hepatic impairment. Participants with hepatic impairment and age/weight‐matched controls with normal hepatic function received a single oral 100‐mg glasdegib dose under fasted conditions. The primary end points were area under the plasma concentration–time curve from time zero to infinity (AUC(inf)) and maximum plasma concentration (C(max)). Twenty‐four participants (8/cohort) were enrolled. Glasdegib plasma exposures in moderate hepatic impairment were similar to controls, with adjusted geometric mean ratios (GMRs) of 110.8% (90% confidence interval [CI], 78.0–157.3) for AUC(inf) and 94.8% (69.9–128.4) for C(max) versus controls. In severe hepatic impairment, glasdegib plasma exposures were lower than controls (AUC(inf) GMR, 75.7%; 90%CI, 51.5–111.0; C(max) GMR, 58.0%; 90%CI, 37.8–89.0). Unbound glasdegib exposures were similar to controls for moderate (AUC(inf,u) GMR, 118.1%; 90%CI, 88.7–157.2; C(max,u) GMR, 101.1%; 90%CI, 78.4–130.3) and severe hepatic impairment (AUC(inf,u) GMR, 116.3%; 90%CI 81.8–165.5; C(max,u) GMR, 89.2%, 90%CI, 60.2–132.3). No treatment‐related adverse events or clinically significant changes in laboratory values, vital signs, or electrocardiograms were observed. Together with previous findings, this suggests glasdegib dose modifications are not required based on hepatic impairment. |
format | Online Article Text |
id | pubmed-8359308 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-83593082021-08-17 Pharmacokinetics and Safety of Glasdegib in Participants With Moderate/Severe Hepatic Impairment: A Phase I, Single‐Dose, Matched Case‐Control Study Masters, Joanna C. LaBadie, Robert R. Salageanu, Joanne Li, Jerry Shaik, Naveed Clin Pharmacol Drug Dev Articles This phase I open‐label trial (NCT03627754) assessed glasdegib pharmacokinetics and safety in otherwise healthy participants with moderate (Child‐Pugh B) or severe (Child‐Pugh C) hepatic impairment. Participants with hepatic impairment and age/weight‐matched controls with normal hepatic function received a single oral 100‐mg glasdegib dose under fasted conditions. The primary end points were area under the plasma concentration–time curve from time zero to infinity (AUC(inf)) and maximum plasma concentration (C(max)). Twenty‐four participants (8/cohort) were enrolled. Glasdegib plasma exposures in moderate hepatic impairment were similar to controls, with adjusted geometric mean ratios (GMRs) of 110.8% (90% confidence interval [CI], 78.0–157.3) for AUC(inf) and 94.8% (69.9–128.4) for C(max) versus controls. In severe hepatic impairment, glasdegib plasma exposures were lower than controls (AUC(inf) GMR, 75.7%; 90%CI, 51.5–111.0; C(max) GMR, 58.0%; 90%CI, 37.8–89.0). Unbound glasdegib exposures were similar to controls for moderate (AUC(inf,u) GMR, 118.1%; 90%CI, 88.7–157.2; C(max,u) GMR, 101.1%; 90%CI, 78.4–130.3) and severe hepatic impairment (AUC(inf,u) GMR, 116.3%; 90%CI 81.8–165.5; C(max,u) GMR, 89.2%, 90%CI, 60.2–132.3). No treatment‐related adverse events or clinically significant changes in laboratory values, vital signs, or electrocardiograms were observed. Together with previous findings, this suggests glasdegib dose modifications are not required based on hepatic impairment. John Wiley and Sons Inc. 2020-12-23 2021-07 /pmc/articles/PMC8359308/ /pubmed/33356019 http://dx.doi.org/10.1002/cpdd.897 Text en © 2020 Pfizer Inc. Clinical Pharmacology in Drug Development published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ (https://creativecommons.org/licenses/by-nc-nd/4.0/) License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made. |
spellingShingle | Articles Masters, Joanna C. LaBadie, Robert R. Salageanu, Joanne Li, Jerry Shaik, Naveed Pharmacokinetics and Safety of Glasdegib in Participants With Moderate/Severe Hepatic Impairment: A Phase I, Single‐Dose, Matched Case‐Control Study |
title | Pharmacokinetics and Safety of Glasdegib in Participants With Moderate/Severe Hepatic Impairment: A Phase I, Single‐Dose, Matched Case‐Control Study |
title_full | Pharmacokinetics and Safety of Glasdegib in Participants With Moderate/Severe Hepatic Impairment: A Phase I, Single‐Dose, Matched Case‐Control Study |
title_fullStr | Pharmacokinetics and Safety of Glasdegib in Participants With Moderate/Severe Hepatic Impairment: A Phase I, Single‐Dose, Matched Case‐Control Study |
title_full_unstemmed | Pharmacokinetics and Safety of Glasdegib in Participants With Moderate/Severe Hepatic Impairment: A Phase I, Single‐Dose, Matched Case‐Control Study |
title_short | Pharmacokinetics and Safety of Glasdegib in Participants With Moderate/Severe Hepatic Impairment: A Phase I, Single‐Dose, Matched Case‐Control Study |
title_sort | pharmacokinetics and safety of glasdegib in participants with moderate/severe hepatic impairment: a phase i, single‐dose, matched case‐control study |
topic | Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8359308/ https://www.ncbi.nlm.nih.gov/pubmed/33356019 http://dx.doi.org/10.1002/cpdd.897 |
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