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Effect of Hepatic Impairment on the Pharmacokinetics of Alectinib
Alectinib is approved and recommended as the preferred first‐line treatment for patients with anaplastic lymphoma kinase (ALK)‐positive non–small cell lung cancer. The effect of hepatic impairment on the pharmacokinetics (PK) of alectinib was assessed with physiologically based PK modeling prospecti...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6282775/ https://www.ncbi.nlm.nih.gov/pubmed/30052269 http://dx.doi.org/10.1002/jcph.1286 |
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author | Morcos, Peter N. Cleary, Yumi Sturm‐Pellanda, Carolina Guerini, Elena Abt, Markus Donzelli, Massimiliano Vazvaei, Faye Balas, Bogdana Parrott, Neil Yu, Li |
author_facet | Morcos, Peter N. Cleary, Yumi Sturm‐Pellanda, Carolina Guerini, Elena Abt, Markus Donzelli, Massimiliano Vazvaei, Faye Balas, Bogdana Parrott, Neil Yu, Li |
author_sort | Morcos, Peter N. |
collection | PubMed |
description | Alectinib is approved and recommended as the preferred first‐line treatment for patients with anaplastic lymphoma kinase (ALK)‐positive non–small cell lung cancer. The effect of hepatic impairment on the pharmacokinetics (PK) of alectinib was assessed with physiologically based PK modeling prospectively and in a clinical study. An open‐label study (NCT02621047) investigated a single 300‐mg dose of alectinib in moderate (n = 8) and severe (n = 8) hepatic impairment (Child‐Pugh B/C), and healthy subjects (n = 12) matched for age, sex, and body weight. Physiologically based PK modeling was conducted prospectively to inform the clinical study design and support the use of a lower dose and extended PK sampling in the study. PK parameters were calculated for alectinib, its major similarly active metabolite, M4, and the combined exposure of alectinib and M4. Unbound concentrations were assessed at 6 and 12 hours postdose. Administration of alectinib to subjects with hepatic impairment increased the area under the plasma concentration–time curve from time 0 to infinity of the combined exposure of alectinib and M4 to 136% (90% confidence interval [CI], 94.7‐196) and 176% (90%CI 98.4‐315), for moderate and severe hepatic impairment, respectively, relative to matched healthy subjects. Unbound concentrations for alectinib and M4 did not appear substantially different between hepatic‐impaired and healthy subjects. Moderate hepatic impairment had only a modest, not clinically significant effect on alectinib exposure, while the higher exposure observed in severe hepatic impairment supports a dose adjustment in this population. |
format | Online Article Text |
id | pubmed-6282775 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-62827752018-12-11 Effect of Hepatic Impairment on the Pharmacokinetics of Alectinib Morcos, Peter N. Cleary, Yumi Sturm‐Pellanda, Carolina Guerini, Elena Abt, Markus Donzelli, Massimiliano Vazvaei, Faye Balas, Bogdana Parrott, Neil Yu, Li J Clin Pharmacol Special Populations Alectinib is approved and recommended as the preferred first‐line treatment for patients with anaplastic lymphoma kinase (ALK)‐positive non–small cell lung cancer. The effect of hepatic impairment on the pharmacokinetics (PK) of alectinib was assessed with physiologically based PK modeling prospectively and in a clinical study. An open‐label study (NCT02621047) investigated a single 300‐mg dose of alectinib in moderate (n = 8) and severe (n = 8) hepatic impairment (Child‐Pugh B/C), and healthy subjects (n = 12) matched for age, sex, and body weight. Physiologically based PK modeling was conducted prospectively to inform the clinical study design and support the use of a lower dose and extended PK sampling in the study. PK parameters were calculated for alectinib, its major similarly active metabolite, M4, and the combined exposure of alectinib and M4. Unbound concentrations were assessed at 6 and 12 hours postdose. Administration of alectinib to subjects with hepatic impairment increased the area under the plasma concentration–time curve from time 0 to infinity of the combined exposure of alectinib and M4 to 136% (90% confidence interval [CI], 94.7‐196) and 176% (90%CI 98.4‐315), for moderate and severe hepatic impairment, respectively, relative to matched healthy subjects. Unbound concentrations for alectinib and M4 did not appear substantially different between hepatic‐impaired and healthy subjects. Moderate hepatic impairment had only a modest, not clinically significant effect on alectinib exposure, while the higher exposure observed in severe hepatic impairment supports a dose adjustment in this population. John Wiley and Sons Inc. 2018-07-27 2018-12 /pmc/articles/PMC6282775/ /pubmed/30052269 http://dx.doi.org/10.1002/jcph.1286 Text en © 2018, The Authors. The Journal of Clinical Pharmacology published by Wiley Periodicals, Inc. on behalf of American College of Clinical Pharmacology This is an open access article under the terms of the http://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 | Special Populations Morcos, Peter N. Cleary, Yumi Sturm‐Pellanda, Carolina Guerini, Elena Abt, Markus Donzelli, Massimiliano Vazvaei, Faye Balas, Bogdana Parrott, Neil Yu, Li Effect of Hepatic Impairment on the Pharmacokinetics of Alectinib |
title | Effect of Hepatic Impairment on the Pharmacokinetics of Alectinib |
title_full | Effect of Hepatic Impairment on the Pharmacokinetics of Alectinib |
title_fullStr | Effect of Hepatic Impairment on the Pharmacokinetics of Alectinib |
title_full_unstemmed | Effect of Hepatic Impairment on the Pharmacokinetics of Alectinib |
title_short | Effect of Hepatic Impairment on the Pharmacokinetics of Alectinib |
title_sort | effect of hepatic impairment on the pharmacokinetics of alectinib |
topic | Special Populations |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6282775/ https://www.ncbi.nlm.nih.gov/pubmed/30052269 http://dx.doi.org/10.1002/jcph.1286 |
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