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

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 metabolit...

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Main Authors: Chishima, H. (Author), Hakamata, J. (Author), Ikemura, S. (Author), Ishikawa, E. (Author), Jibiki, A. (Author), Kawazoe, H. (Author), Kimura, M. (Author), Kuniyoshi, O. (Author), Muramatsu, H. (Author), Nakada, H. (Author), Nakajima, H. (Author), Nakamura, T. (Author), Nakaya, N. (Author), Sato, I. (Author), Suehiro, N. (Author), Suzuki, S. (Author), Yokoyama, Y. (Author)
Format: Article
Language:English
Published: Elsevier B.V. 2022
Subjects:
Online Access:View Fulltext in Publisher
LEADER 04095nam a2200661Ia 4500
001 10.1016-j.jchromb.2022.123245
008 220706s2022 CNT 000 0 und d
020 |a 15700232 (ISSN) 
245 1 0 |a 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 
260 0 |b Elsevier B.V.  |c 2022 
856 |z View Fulltext in Publisher  |u https://doi.org/10.1016/j.jchromb.2022.123245 
520 3 |a 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. © 2022 The Authors 
650 0 4 |a Active metabolites 
650 0 4 |a Amino acids 
650 0 4 |a Biological organs 
650 0 4 |a Biomolecules 
650 0 4 |a Diseases 
650 0 4 |a Drug products 
650 0 4 |a Enzymes 
650 0 4 |a Epidermal growth factor receptors 
650 0 4 |a Epidermal growth factor receptor-tyrosine kinase inhibitor 
650 0 4 |a Epidermal growth factor receptor-tyrosine kinase inhibitors 
650 0 4 |a Human serum 
650 0 4 |a Human serum 
650 0 4 |a Lc.ms/ms 
650 0 4 |a LC-MS/MS 
650 0 4 |a LC-MS-MS 
650 0 4 |a Liquid chromatography 
650 0 4 |a Mass spectrometry 
650 0 4 |a Metabolites 
650 0 4 |a Non small cell lung cancer 
650 0 4 |a Non-small cell lung cancer 
650 0 4 |a Patient monitoring 
650 0 4 |a Patient treatment 
650 0 4 |a Precipitation (chemical) 
650 0 4 |a Protein precipitation 
650 0 4 |a Protein precipitation 
650 0 4 |a Receptor-tyrosine kinase 
650 0 4 |a Safety factor 
650 0 4 |a Tyrosine kinase inhibitor 
700 1 0 |a Chishima, H.  |e author 
700 1 0 |a Hakamata, J.  |e author 
700 1 0 |a Ikemura, S.  |e author 
700 1 0 |a Ishikawa, E.  |e author 
700 1 0 |a Jibiki, A.  |e author 
700 1 0 |a Kawazoe, H.  |e author 
700 1 0 |a Kimura, M.  |e author 
700 1 0 |a Kuniyoshi, O.  |e author 
700 1 0 |a Muramatsu, H.  |e author 
700 1 0 |a Nakada, H.  |e author 
700 1 0 |a Nakajima, H.  |e author 
700 1 0 |a Nakamura, T.  |e author 
700 1 0 |a Nakaya, N.  |e author 
700 1 0 |a Sato, I.  |e author 
700 1 0 |a Suehiro, N.  |e author 
700 1 0 |a Suzuki, S.  |e author 
700 1 0 |a Yokoyama, Y.  |e author 
773 |t Journal of Chromatography B: Analytical Technologies in the Biomedical and Life Sciences