Development and validation of a new liquid chromatography-tandem mass spectrometry assay for the simultaneous quantification of afatinib, dacomitinib, osimertinib, and the active metabolites of osimertinib in human serum

•A novel method for therapeutic drug monitoring of newer generation EGFR-TKIs.•Simultaneous quantification of parent compounds and active metabolites of EGFR-TKIs.•A simple sample preparation method without causing apparent matrix effect.•The method has high accuracy and reliability and complies wit...

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Published in:Journal of chromatography. B, Analytical technologies in the biomedical and life sciences Analytical technologies in the biomedical and life sciences, 2022-05, Vol.1199, p.123245-123245, Article 123245
Main Authors: Ishikawa, Emi, Yokoyama, Yuta, Chishima, Haruna, Kuniyoshi, Ouki, Sato, Itaru, Nakaya, Naoki, Nakajima, Hideo, Kimura, Motonori, Hakamata, Jun, Suehiro, Naoya, Nakada, Hideo, Ikemura, Shinnosuke, Jibiki, Aya, Kawazoe, Hitoshi, Muramatsu, Hiroshi, Suzuki, Sayo, Nakamura, Tomonori
Format: Article
Language:English
Subjects:
Acrylamides
Afatinib
Aniline Compounds
Carcinoma, Non-Small-Cell Lung - drug therapy
Chromatography, Liquid - methods
Epidermal growth factor receptor-tyrosine kinase inhibitors
ErbB Receptors
Human serum
Humans
LC-MS/MS
Lung Neoplasms - drug therapy
Mutation
Non-small cell lung cancer
Protein Kinase Inhibitors
Protein precipitation
Quinazolinones
Tandem Mass Spectrometry - methods
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Summary:•A novel method for therapeutic drug monitoring of newer generation EGFR-TKIs.•Simultaneous quantification of parent compounds and active metabolites of EGFR-TKIs.•A simple sample preparation method without causing apparent matrix effect.•The method has high accuracy and reliability and complies with the FDA guidelines. Reports on the therapeutic drug monitoring (TDM) of second- and third-generation epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) in non-small cell lung cancer patients are limited and are required to improve the safety of EGFR-TKI therapy. Some EGFR-TKIs have active metabolites with similar or higher potency compared with the parent compounds; thus, monitoring the parent compound as well as its active metabolites is essential for truly effective TDM. In this study, we developed and validated a method that simultaneously quantifies second- and third-generation EGFR-TKIs (afatinib, dacomitinib, and osimertinib) and the active metabolites of osimertinib, AZ5104 and AZ7550, in the human serum using liquid chromatography-tandem mass spectrometry (LC-MS/MS). The clinical application of the method was also evaluated. The analytes were extracted from a 100 μL serum sample using a simple protein precipitation method and analyzed using LC-MS/MS. Excellent linearity of calibration curves was observed at ranges of 2.5–125.0 ng/mL for afatinib, 2.5–125.0 ng/mL for dacomitinib, 4.0–800.0 ng/mL for osimertinib, 1.0–125.0 ng/mL for AZ5104, and 2.5–125.0 ng/mL for AZ7550. The precision and accuracy were below 14.9% and within ± 14.9% of the nominal concentrations, respectively. The mean recovery was higher than 94.7% and the coefficient of variation (CV) was lower than 8.3%. The mean internal-standard normalized matrix factors ranged from 94.6 to 111.9%, and the CVs were lower than 9.7%. This analytical method met the acceptance criteria of the U.S. Food and Drug Administration guidelines. The method was also successfully applied to the analysis of 45 clinical samples; it supports the efficient and valuable analysis for TDM investigations of EGFR-TKIs.
ISSN:1570-0232
1873-376X
DOI:10.1016/j.jchromb.2022.123245