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

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.

Quantitation of osimertinib, alectinib and lorlatinib in human cerebrospinal fluid by UPLC-MS/MS

“…Furthermore, lorlatinib and osimertinib have comparable acidity, with a pK a of 4.9 and 4.4 (aniline) respectively [33,34]. In human plasma, the instability of osimertinib is thought to be secondary to the Michael addition reaction between osimertinib and cysteine in the plasma matrix [35]. However, this is not likely happening in human CSF, as cysteine normally is not present in this matrix [36].…”

Identification of lncRNAs associated with T cells as potential biomarkers and therapeutic targets in lung adenocarcinoma

“…Lung cancer is the second most prevalent cancer and leading cancer killer worldwide [1]. Clinical data demonstrate that approximately 85% of all lung cancers are non-small cell lung cancer (NSCLC), with the most predominant type being lung adenocarcinoma (LUAD) [2,3]. LUAD progresses rapidly with micrometastatic foci and has a high recurrence rate and an increased metastatic rate.…”

An LC–MS/MS Analytical Method for Quantifying Tepotinib in Human Liver Microsomes: Application to In Vitro and In Silico Metabolic Stability Estimation

“…Lung cancer is considered one of the greatest widespread malignancies, as two million patients are diagnosed with it each year globally, causing 20% of all cancer deaths [2]. Among lung cancer cases, 90% are non-small cell lung carcinomas (NSCLC) that have numerous subtypes initiated by a range of activated oncogenes [3][4][5]. Although progress in developing a new drug series for cancer treatment has been slow, current molecular targeting strategies used in tumor suppressor genes and modulating oncogenes contributed to the improved prognosis of patients [6].…”