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Absorption, metabolism, excretion, and safety of [(14)C]almonertinib in healthy Chinese subjects
BACKGROUND: Almonertinib Mesilate Tablets (HS-10296, Hansoh Pharma, Shanghai, China) is a novel and selective third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI). A phase I study of almonertinib in patients with non-small cell lung cancer (NSCLC) demonstrated a lin...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
AME Publishing Company
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8184462/ https://www.ncbi.nlm.nih.gov/pubmed/34164501 http://dx.doi.org/10.21037/atm-21-1606 |
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author | Zhou, Chen Xie, Lijun Liu, Wei Zhang, Lingling Zhou, Sufeng Wang, Lu Chen, Juan Li, Huan Zhao, Yuqing Zhu, Bei Ding, Sijia Zhang, Chen Shao, Feng |
author_facet | Zhou, Chen Xie, Lijun Liu, Wei Zhang, Lingling Zhou, Sufeng Wang, Lu Chen, Juan Li, Huan Zhao, Yuqing Zhu, Bei Ding, Sijia Zhang, Chen Shao, Feng |
author_sort | Zhou, Chen |
collection | PubMed |
description | BACKGROUND: Almonertinib Mesilate Tablets (HS-10296, Hansoh Pharma, Shanghai, China) is a novel and selective third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI). A phase I study of almonertinib in patients with non-small cell lung cancer (NSCLC) demonstrated a linear metabolic trend, a good tolerability/safety profile, and preliminary antitumor activity. However, the metabolism, excretion, and substance balance of almonertinib has not been clearly determined. Here, we investigated the pharmacokinetic characteristics and safety profile of almonertinib following a single oral dose (110 mg/50 µCi) in healthy Chinese male participants. METHODS: Total radioactivity (TRA) in whole blood, plasma, urine, and feces was measured by utilizing a liquid scintillation counter to obtain almonertinib substance balance data. The pharmacokinetic parameters of [(14)C]almonertinib and the parent drug almonertinib in whole blood and plasma were analyzed with noncompartmental analysis in the WinNonlin software (Pharsight Corp). The major metabolites in plasma, urine, and feces were analyzed by high-performance liquid chromatography (HPLC) coupled with an online or offline isotope detector. The safety of the drug was evaluated after administration. RESULTS: The safety and tolerability of a single oral dose of 110 mg/50 µCi [(14)C] almonertinib suspension were good in healthy Chinese male participants. There was no significant abnormality or special adverse reaction. TRA peaked quickly in plasma, with a T(max) of 4.0 h; however, TRA was cleared slowly in vivo, with a mean terminal elimination phase (half-life, T(1/2)) of up to 863 h. In addition to the parent drug, a total of 26 metabolites in blood, urine, and feces were analyzed. In plasma, parent drug was the major drug-related component, accounting for 69.97% of TRA, and M440 (almonertinib-M2 demethyl product) was the major metabolite, accounting for 5.08% of TRA; in urine, parent drug accounted for 0.48% of the dose administered and HAS-719 was the major metabolite, accounting for 1.20% of the administered dose; in feces, parent drug was about 8.61% of the dose administered and HAS-719 was the major metabolite, accounting for 12.33% of the administered dose, which was followed by M541a/M470a and M617/M575, accounting for 11.8% and 6.76% of the administered dose, respectively. CONCLUSIONS: Almonertinib has a good safety profile, with parent drug as its main circulating component. almonertinib is extensively metabolized in vivo before excretion and is excreted as a parent drug and metabolites mainly via feces. TRIAL REGISTRATION: The trial registration number: CTR20192291. |
format | Online Article Text |
id | pubmed-8184462 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | AME Publishing Company |
record_format | MEDLINE/PubMed |
spelling | pubmed-81844622021-06-22 Absorption, metabolism, excretion, and safety of [(14)C]almonertinib in healthy Chinese subjects Zhou, Chen Xie, Lijun Liu, Wei Zhang, Lingling Zhou, Sufeng Wang, Lu Chen, Juan Li, Huan Zhao, Yuqing Zhu, Bei Ding, Sijia Zhang, Chen Shao, Feng Ann Transl Med Original Article BACKGROUND: Almonertinib Mesilate Tablets (HS-10296, Hansoh Pharma, Shanghai, China) is a novel and selective third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI). A phase I study of almonertinib in patients with non-small cell lung cancer (NSCLC) demonstrated a linear metabolic trend, a good tolerability/safety profile, and preliminary antitumor activity. However, the metabolism, excretion, and substance balance of almonertinib has not been clearly determined. Here, we investigated the pharmacokinetic characteristics and safety profile of almonertinib following a single oral dose (110 mg/50 µCi) in healthy Chinese male participants. METHODS: Total radioactivity (TRA) in whole blood, plasma, urine, and feces was measured by utilizing a liquid scintillation counter to obtain almonertinib substance balance data. The pharmacokinetic parameters of [(14)C]almonertinib and the parent drug almonertinib in whole blood and plasma were analyzed with noncompartmental analysis in the WinNonlin software (Pharsight Corp). The major metabolites in plasma, urine, and feces were analyzed by high-performance liquid chromatography (HPLC) coupled with an online or offline isotope detector. The safety of the drug was evaluated after administration. RESULTS: The safety and tolerability of a single oral dose of 110 mg/50 µCi [(14)C] almonertinib suspension were good in healthy Chinese male participants. There was no significant abnormality or special adverse reaction. TRA peaked quickly in plasma, with a T(max) of 4.0 h; however, TRA was cleared slowly in vivo, with a mean terminal elimination phase (half-life, T(1/2)) of up to 863 h. In addition to the parent drug, a total of 26 metabolites in blood, urine, and feces were analyzed. In plasma, parent drug was the major drug-related component, accounting for 69.97% of TRA, and M440 (almonertinib-M2 demethyl product) was the major metabolite, accounting for 5.08% of TRA; in urine, parent drug accounted for 0.48% of the dose administered and HAS-719 was the major metabolite, accounting for 1.20% of the administered dose; in feces, parent drug was about 8.61% of the dose administered and HAS-719 was the major metabolite, accounting for 12.33% of the administered dose, which was followed by M541a/M470a and M617/M575, accounting for 11.8% and 6.76% of the administered dose, respectively. CONCLUSIONS: Almonertinib has a good safety profile, with parent drug as its main circulating component. almonertinib is extensively metabolized in vivo before excretion and is excreted as a parent drug and metabolites mainly via feces. TRIAL REGISTRATION: The trial registration number: CTR20192291. AME Publishing Company 2021-05 /pmc/articles/PMC8184462/ /pubmed/34164501 http://dx.doi.org/10.21037/atm-21-1606 Text en 2021 Annals of Translational Medicine. All rights reserved. https://creativecommons.org/licenses/by-nc-nd/4.0/Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0 (https://creativecommons.org/licenses/by-nc-nd/4.0/) . |
spellingShingle | Original Article Zhou, Chen Xie, Lijun Liu, Wei Zhang, Lingling Zhou, Sufeng Wang, Lu Chen, Juan Li, Huan Zhao, Yuqing Zhu, Bei Ding, Sijia Zhang, Chen Shao, Feng Absorption, metabolism, excretion, and safety of [(14)C]almonertinib in healthy Chinese subjects |
title | Absorption, metabolism, excretion, and safety of [(14)C]almonertinib in healthy Chinese subjects |
title_full | Absorption, metabolism, excretion, and safety of [(14)C]almonertinib in healthy Chinese subjects |
title_fullStr | Absorption, metabolism, excretion, and safety of [(14)C]almonertinib in healthy Chinese subjects |
title_full_unstemmed | Absorption, metabolism, excretion, and safety of [(14)C]almonertinib in healthy Chinese subjects |
title_short | Absorption, metabolism, excretion, and safety of [(14)C]almonertinib in healthy Chinese subjects |
title_sort | absorption, metabolism, excretion, and safety of [(14)c]almonertinib in healthy chinese subjects |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8184462/ https://www.ncbi.nlm.nih.gov/pubmed/34164501 http://dx.doi.org/10.21037/atm-21-1606 |
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