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Characterization of the pharmacokinetics of entrectinib and its active M5 metabolite in healthy volunteers and patients with solid tumors
Background: Entrectinib is an oral, CNS-active, potent inhibitor of tyrosine receptor kinases A/B/C, tyrosine kinase ROS proto-oncogene 1, and anaplastic lymphoma kinase approved for use in patients with solid tumors. We describe 3 clinical studies, including one investigating the single/multiple do...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Springer US
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8068699/ https://www.ncbi.nlm.nih.gov/pubmed/33462752 http://dx.doi.org/10.1007/s10637-020-01047-5 |
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author | Meneses-Lorente, Georgina Bentley, Darren Guerini, Elena Kowalski, Karey Chow-Maneval, Edna Yu, Li Brink, Andreas Djebli, Nassim Mercier, Francois Buchheit, Vincent Phipps, Alex |
author_facet | Meneses-Lorente, Georgina Bentley, Darren Guerini, Elena Kowalski, Karey Chow-Maneval, Edna Yu, Li Brink, Andreas Djebli, Nassim Mercier, Francois Buchheit, Vincent Phipps, Alex |
author_sort | Meneses-Lorente, Georgina |
collection | PubMed |
description | Background: Entrectinib is an oral, CNS-active, potent inhibitor of tyrosine receptor kinases A/B/C, tyrosine kinase ROS proto-oncogene 1, and anaplastic lymphoma kinase approved for use in patients with solid tumors. We describe 3 clinical studies, including one investigating the single/multiple dose pharmacokinetics of entrectinib in patients and two studies in healthy volunteers investigating the absorption/distribution/metabolism/excretion (ADME) of entrectinib, its relative bioavailability, and effect of food on pharmacokinetics. Methods: The patient study is open-label with dose-escalation and expansion phases. Volunteers received entrectinib (100–400 mg/m(2), and 600–800 mg) once daily with food in continuous 28-day cycles. In the ADME study, volunteers received a single oral dose of [(14)C]entrectinib 600 mg. In the third study, volunteers received single doses of entrectinib 600 mg as the research and marketed formulations in the fasted state (Part 1), and the marketed formulation in the fed and fasted states (Part 2). Entrectinib and its major active metabolite M5 were assessed in all studies. Results: Entrectinib was absorbed in a dose-dependent manner with maximum concentrations at ~4 h postdose and an elimination half-life of ~20 h. Entrectinib was cleared mainly through metabolism and both entrectinib and metabolites were eliminated mainly in feces (minimal renal excretion). At steady-state, the M5-to-entrectinib AUC ratio was 0.5 (with 600 mg entrectinib research formulation in patients). The research and marketed formulations were bioequivalent and food had no relevant effect on pharmacokinetics. Conclusions: Entrectinib is well absorbed, with linear PK that is suitable for once-daily dosing, and can be taken with or without food. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s10637-020-01047-5. |
format | Online Article Text |
id | pubmed-8068699 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Springer US |
record_format | MEDLINE/PubMed |
spelling | pubmed-80686992021-05-05 Characterization of the pharmacokinetics of entrectinib and its active M5 metabolite in healthy volunteers and patients with solid tumors Meneses-Lorente, Georgina Bentley, Darren Guerini, Elena Kowalski, Karey Chow-Maneval, Edna Yu, Li Brink, Andreas Djebli, Nassim Mercier, Francois Buchheit, Vincent Phipps, Alex Invest New Drugs Phase I Studies Background: Entrectinib is an oral, CNS-active, potent inhibitor of tyrosine receptor kinases A/B/C, tyrosine kinase ROS proto-oncogene 1, and anaplastic lymphoma kinase approved for use in patients with solid tumors. We describe 3 clinical studies, including one investigating the single/multiple dose pharmacokinetics of entrectinib in patients and two studies in healthy volunteers investigating the absorption/distribution/metabolism/excretion (ADME) of entrectinib, its relative bioavailability, and effect of food on pharmacokinetics. Methods: The patient study is open-label with dose-escalation and expansion phases. Volunteers received entrectinib (100–400 mg/m(2), and 600–800 mg) once daily with food in continuous 28-day cycles. In the ADME study, volunteers received a single oral dose of [(14)C]entrectinib 600 mg. In the third study, volunteers received single doses of entrectinib 600 mg as the research and marketed formulations in the fasted state (Part 1), and the marketed formulation in the fed and fasted states (Part 2). Entrectinib and its major active metabolite M5 were assessed in all studies. Results: Entrectinib was absorbed in a dose-dependent manner with maximum concentrations at ~4 h postdose and an elimination half-life of ~20 h. Entrectinib was cleared mainly through metabolism and both entrectinib and metabolites were eliminated mainly in feces (minimal renal excretion). At steady-state, the M5-to-entrectinib AUC ratio was 0.5 (with 600 mg entrectinib research formulation in patients). The research and marketed formulations were bioequivalent and food had no relevant effect on pharmacokinetics. Conclusions: Entrectinib is well absorbed, with linear PK that is suitable for once-daily dosing, and can be taken with or without food. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s10637-020-01047-5. Springer US 2021-01-18 2021 /pmc/articles/PMC8068699/ /pubmed/33462752 http://dx.doi.org/10.1007/s10637-020-01047-5 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open Access This 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 | Phase I Studies Meneses-Lorente, Georgina Bentley, Darren Guerini, Elena Kowalski, Karey Chow-Maneval, Edna Yu, Li Brink, Andreas Djebli, Nassim Mercier, Francois Buchheit, Vincent Phipps, Alex Characterization of the pharmacokinetics of entrectinib and its active M5 metabolite in healthy volunteers and patients with solid tumors |
title | Characterization of the pharmacokinetics of entrectinib and its active M5 metabolite in healthy volunteers and patients with solid tumors |
title_full | Characterization of the pharmacokinetics of entrectinib and its active M5 metabolite in healthy volunteers and patients with solid tumors |
title_fullStr | Characterization of the pharmacokinetics of entrectinib and its active M5 metabolite in healthy volunteers and patients with solid tumors |
title_full_unstemmed | Characterization of the pharmacokinetics of entrectinib and its active M5 metabolite in healthy volunteers and patients with solid tumors |
title_short | Characterization of the pharmacokinetics of entrectinib and its active M5 metabolite in healthy volunteers and patients with solid tumors |
title_sort | characterization of the pharmacokinetics of entrectinib and its active m5 metabolite in healthy volunteers and patients with solid tumors |
topic | Phase I Studies |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8068699/ https://www.ncbi.nlm.nih.gov/pubmed/33462752 http://dx.doi.org/10.1007/s10637-020-01047-5 |
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