Instability Mechanism of Osimertinib in Plasma and a Solving Strategy in the Pharmacokinetics Study
Osimertinib is a third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) and a star medication used to treat non-small-cell lung carcinomas (NSCLCs). It has caused broad public concern that osimertinib has relatively low stability in plasma. We explored why osimertinib...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-07-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2022.928983/full |
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| author | Zheng Yuan Xin Yu Siyang Wu Xiaonan Wu Qiutao Wang Wenhao Cheng Weiyu Hu Chen Kang Wei Yang Yingfei Li Xiao-Yang Zhou |
| author_facet | Zheng Yuan Xin Yu Siyang Wu Xiaonan Wu Qiutao Wang Wenhao Cheng Weiyu Hu Chen Kang Wei Yang Yingfei Li Xiao-Yang Zhou |
| author_sort | Zheng Yuan |
| collection | DOAJ |
| description | Osimertinib is a third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) and a star medication used to treat non-small-cell lung carcinomas (NSCLCs). It has caused broad public concern that osimertinib has relatively low stability in plasma. We explored why osimertinib and its primary metabolites AZ-5104 and AZ-7550 are unstable in rat plasma. Our results suggested that it is the main reason inducing their unstable phenomenon that the Michael addition reaction was putatively produced between the Michael acceptor of osimertinib and the cysteine in the plasma matrix. Consequently, we identified a method to stabilize osimertinib and its metabolite contents in plasma. The assay was observed to enhance the stability of osimertinib, AZ-5104, and AZ-7550 significantly. The validated method was subsequently applied to perform the pharmacokinetic study for osimertinib in rats with the newly established, elegant, and optimized ultra-performance liquid chromatography–tandem mass spectrometer (UPLC-MS/MS) strategy. The assay was assessed for accuracy, precision, matrix effects, recovery, and stability. This study can help understand the pharmacological effects of osimertinib and promote a solution for the similar problem of other Michael acceptor-contained third-generation EGFR-TKI. |
| first_indexed | 2024-12-10T23:09:00Z |
| format | Article |
| id | doaj.art-44685d79e6654697ab04705d2368467e |
| institution | Directory Open Access Journal |
| issn | 1663-9812 |
| language | English |
| last_indexed | 2024-12-10T23:09:00Z |
| publishDate | 2022-07-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Pharmacology |
| spelling | doaj.art-44685d79e6654697ab04705d2368467e2022-12-22T01:29:59ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122022-07-011310.3389/fphar.2022.928983928983Instability Mechanism of Osimertinib in Plasma and a Solving Strategy in the Pharmacokinetics StudyZheng Yuan0Xin Yu1Siyang Wu2Xiaonan Wu3Qiutao Wang4Wenhao Cheng5Weiyu Hu6Chen Kang7Wei Yang8Yingfei Li9Xiao-Yang Zhou10Center for DMPK Research of Herbal Medicines, Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, ChinaCenter for DMPK Research of Herbal Medicines, Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, ChinaCenter for DMPK Research of Herbal Medicines, Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, ChinaDepartment of Oncology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, ChinaSchool of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, ChinaSchool of Chinese Pharmacy, Beijing University of Chinese Medicine, Beijing, ChinaDepartment of Hepatobiliary Pancreatic Surgery, The Affiliated Hospital of Qingdao University, Qingdao, ChinaCenter for DMPK Research of Herbal Medicines, Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, ChinaCenter for DMPK Research of Herbal Medicines, Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, ChinaCenter for DMPK Research of Herbal Medicines, Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, ChinaThe Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology of National Health Commission, Beijing, ChinaOsimertinib is a third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) and a star medication used to treat non-small-cell lung carcinomas (NSCLCs). It has caused broad public concern that osimertinib has relatively low stability in plasma. We explored why osimertinib and its primary metabolites AZ-5104 and AZ-7550 are unstable in rat plasma. Our results suggested that it is the main reason inducing their unstable phenomenon that the Michael addition reaction was putatively produced between the Michael acceptor of osimertinib and the cysteine in the plasma matrix. Consequently, we identified a method to stabilize osimertinib and its metabolite contents in plasma. The assay was observed to enhance the stability of osimertinib, AZ-5104, and AZ-7550 significantly. The validated method was subsequently applied to perform the pharmacokinetic study for osimertinib in rats with the newly established, elegant, and optimized ultra-performance liquid chromatography–tandem mass spectrometer (UPLC-MS/MS) strategy. The assay was assessed for accuracy, precision, matrix effects, recovery, and stability. This study can help understand the pharmacological effects of osimertinib and promote a solution for the similar problem of other Michael acceptor-contained third-generation EGFR-TKI.https://www.frontiersin.org/articles/10.3389/fphar.2022.928983/fullosimertinibplasma stabilityUPLC-MS/MSacetonitrilecysteinenon-small-cell lung cancer |
| spellingShingle | Zheng Yuan Xin Yu Siyang Wu Xiaonan Wu Qiutao Wang Wenhao Cheng Weiyu Hu Chen Kang Wei Yang Yingfei Li Xiao-Yang Zhou Instability Mechanism of Osimertinib in Plasma and a Solving Strategy in the Pharmacokinetics Study Frontiers in Pharmacology osimertinib plasma stability UPLC-MS/MS acetonitrile cysteine non-small-cell lung cancer |
| title | Instability Mechanism of Osimertinib in Plasma and a Solving Strategy in the Pharmacokinetics Study |
| title_full | Instability Mechanism of Osimertinib in Plasma and a Solving Strategy in the Pharmacokinetics Study |
| title_fullStr | Instability Mechanism of Osimertinib in Plasma and a Solving Strategy in the Pharmacokinetics Study |
| title_full_unstemmed | Instability Mechanism of Osimertinib in Plasma and a Solving Strategy in the Pharmacokinetics Study |
| title_short | Instability Mechanism of Osimertinib in Plasma and a Solving Strategy in the Pharmacokinetics Study |
| title_sort | instability mechanism of osimertinib in plasma and a solving strategy in the pharmacokinetics study |
| topic | osimertinib plasma stability UPLC-MS/MS acetonitrile cysteine non-small-cell lung cancer |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2022.928983/full |
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