首页|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

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

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  • NSTL
  • Elsevier
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 mu L 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.

LC-MSMSNon-small cell lung cancerEpidermal growth factor receptor-tyrosine kinase inhibitorsHuman serumProtein precipitationTYROSINE KINASE INHIBITORSHUMAN PLASMAEGFR INHIBITORSCLINICAL PHARMACOKINETICSRAPID-DETERMINATIONOPEN-LABELPHASE-IGEFITINIBERLOTINIBCRIZOTINIB

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

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2022

10.1016/j.jchromb.2022.123245

Journal of chromatography

Journal of chromatography

ISSN：1570-0232
年,卷(期)：2022.1199
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