Instability Mechanism of Osimertinib in Plasma and a Solving Strategy in the Pharmacokinetics Study

Zheng Yuan; Xin Yu; Siyang Wu; Xiaonan Wu; Qiutao Wang; Wenhao Cheng; Weiyu Hu; Chen Kang; Wei Yang; Yingfei Li; Xiao-Yang Zhou

doi:10.3389/fphar.2022.928983

Instability Mechanism of Osimertinib in Plasma and a Solving Strategy in the Pharmacokinetics Study

Front Pharmacol. 2022 Jul 22:13:928983. doi: 10.3389/fphar.2022.928983. eCollection 2022.

Authors

Zheng Yuan¹, Xin Yu¹, Siyang Wu¹, Xiaonan Wu², Qiutao Wang³, Wenhao Cheng⁴, Weiyu Hu⁵, Chen Kang¹, Wei Yang¹, Yingfei Li¹, Xiao-Yang Zhou⁶

Affiliations

¹ Center for DMPK Research of Herbal Medicines, Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, China.
² Department of Oncology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, China.
³ School of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, China.
⁴ School of Chinese Pharmacy, Beijing University of Chinese Medicine, Beijing, China.
⁵ Department of Hepatobiliary Pancreatic Surgery, The Affiliated Hospital of Qingdao University, Qingdao, China.
⁶ The 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, China.

Abstract

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.

Keywords: UPLC-MS/MS; acetonitrile; cysteine; non-small-cell lung cancer; osimertinib; plasma stability.