Aim: Gefitinib, erlotinib, icotinib, crizotinib, lapatinib and apatinib are targeted cancer therapy agents acting through inhibition of tyrosine kinase. Method for quantifying these six drugs in human plasma of patients was required. Materials & methods: An HPLC-Q-Orbitrap method (based on HPLC–MS/MS) was developed and validated for the simultaneous detection and quantitation of six tyrosine kinase inhibitors in human plasma. Sample was extracted by liquid–liquid extraction (ethyl acetate: tert-Butyl methyl ether, 1:1 v/v). The method shows a high level of accuracy and reproducibility. The lower limit of quantification was 0.02 ng/ml for apatinib, 0.1 ng/ml for crizotinib, 2.0 ng/ml for lapatinib and 0.05 ng/ml for erlotinib, gefitinib and icotinib. This method was successfully used for apatinib monitoring in plasma of patients with NSCLC. Conclusion: This simple and reproducible method has potential for monitoring of tyrosine kinase inhibitors in patients’ plasma.

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References

1 Moyer JD, Barbacci EG, Iwata KK et al. Induction of apoptosis and cell cycle arrest by CP-358,774, an inhibitor of epidermal growth factor receptor tyrosine kinase. Cancer Res. 57(21), 4838–4848 (1997).
Medline CASGoogle Scholar
2 Glade-Bender J, Kandel JJ, Yamashiro DJ. VEGF blocking therapy in the treatment of cancer. Expert Opin. Biol. Ther. 3(2), 263–276 (2003).
Medline CASGoogle Scholar
3 Kwak EL, Bang YJ, Camidge DR et al. Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N. Engl. J. Med. 363(18), 1693–1703 (2010).
Medline CASGoogle Scholar
4 Hoelder S, Clarke PA, Workman P. Discovery of small molecule cancer drugs: successes, challenges and opportunities. Mol. Oncol. 6(2), 155–176 (2012).
Medline CASGoogle Scholar
5 Kris MG, Natale RB, Herbst RS et al. Efficacy of gefitinib, an inhibitor of the epidermal growth factor receptor tyrosine kinase, in symptomatic patients with non-small cell lung cancer: a randomized trial. JAMA 290(16), 2149–2158 (2003).
Medline CASGoogle Scholar
6 Ciardiello F, Tortora G. A novel approach in the treatment of cancer: targeting the epidermal growth factor receptor. Clin. Cancer Res. 7(10), 2958–2970 (2001).
Medline CASGoogle Scholar
7 Hidalgo M, Siu LL, Nemunaitis J et al. Phase I and pharmacologic study of OSI-774, an epidermal growth factor receptor tyrosine kinase inhibitor, in patients with advanced solid malignancies. J. Clin. Oncol. 19(13), 3267–3279 (2001).
Medline CASGoogle Scholar
8 Huo ZJ, Wang SJ, Wang ZQ et al. Novel nanosystem to enhance the antitumor activity of lapatinib in breast cancer treatment: therapeutic efficacy evaluation. Cancer Sci. 106(10), 1429–1437 (2015).
Medline CASGoogle Scholar
9 Ding L, Li QJ, You KY, Jiang ZM, Yao HR. The use of apatinib in treating nonsmall-cell lung cancer case report and review of literature. Medicine 95(20), e3598 (2016).
Medline CASGoogle Scholar
10 Sandborn WJ, Hanauer SB, Pierre-Louis B, Lichtenstein GR. certolizumab pegol plasma concentration and clinical remission in Crohn's disease. Gastroenterology 142(Suppl. 1), S563 (2012).
Google Scholar
11 Corsonello A, Pedone C, Incalz RA. Age-related pharmacokinetic and pharmacodynamic changes and related risk of adverse drug reactions. Curr. Med. Chem. 17, 14 (2010).
Google Scholar
12 Cimino GD, Pan CX, Henderson PT. Personalized medicine for targeted and platinum-based chemotherapy of lung and bladder cancer. Bioanalysis 5(3), 369–391 (2013).
CASGoogle Scholar
13 Zheng N, Zhao C, He XR et al. Simultaneous determination of gefitinib and its major metabolites in mouse plasma by HPLC–MS/MS and its application to a pharmacokinetics study. J. Chromatogr. B Analyt. Technol. Biomed. Life Sci. 1011, 215–222 (2016).
Medline CASGoogle Scholar
14 Lankheet NA, Schaake EE, Rosing H et al. Quantitative determination of erlotinib and O-desmethyl erlotinib in human EDTA plasma and lung tumor tissue. Bioanalysis 4(21), 2563–2577 (2012).
CASGoogle Scholar
15 Liu D, Jiang J, Hu P, Tan F, Wang Y. Quantitative determination of icotinib in human plasma and urine using liquid chromatography coupled to tandem mass spectrometry. J. Chromatogr. B Analyt. Technol. Biomed. Life Sci. 877(30), 3781–3786 (2009).
Medline CASGoogle Scholar
16 Roberts MS, Turner DC, Broniscer A, Stewart CF. Determination of crizotinib in human and mouse plasma by liquid chromatography electrospray ionization-tandem mass spectrometry (LC-ESI-MS/MS). J. Chromatogr. B 960, 151–157 (2014).
Medline CASGoogle Scholar
17 Musijowski J, Filist M, Rudzki PJ. Sensitive single quadrupole LC/MS method for determination of lapatinib in human plasma. Acta Pol. Pharm. 71(6), 1029–1036 (2014).
MedlineGoogle Scholar
18 Ding J, Chen X, Dai X, Zhong D. Simultaneous determination of apatinib and its four major metabolites in human plasma using liquid chromatography–tandem mass spectrometry and its application to a pharmacokinetic study. J. Chromatogr. B Analyt. Technol. Biomed. Life Sci. 895–896, 108–115 (2012).
Medline CASGoogle Scholar
19 Venugopal N, Reddy AVB, Madhavi G. Development and validation of a systematic UPLC–MS/MS method for simultaneous determination of three phenol impurities in ritonavir. J. Pharmaceut. Biomed. 90, 127–133 (2014).
Medline CASGoogle Scholar
20 ThermoFisher. www.thermofisher.com/content/dam/tfs/ATG/CMD/CMD%20Documents/HUPO-2011-Hao-P1123-Final.pdf.
Google Scholar
21 Sturm RM, Jones BR, Mulvana DE, Lowes S. HRMS using a Q-Exactive series mass spectrometer for regulated quantitative bioanalysis: how, when, and why to implement. Bioanalysis 8(16), 1709–1721 (2016).
CASGoogle Scholar
22 Guidance for Industry Bioanalytical Method Validation. US Department of Health and Human Services, US FDA (2001). www.fda.gov/downloads/Drugs/Guidance/ucm070107.pdf.
Google Scholar
23 Dolan JW. When should an internal standard be used? LCGC N. Am. 30(6), 474 (2012).
CASGoogle Scholar
24 Lynch KL. CLSI C62-A: a new standard for clinical mass spectrometry. Clin. Chem. 62(1), 24–29 (2016).
Medline CASGoogle Scholar
25 Yang ZZ, Wang L, Xu MC, Gu JK, Yu LS, Zeng S. Simultaneous analysis of gemfibrozil, morphine, and its two active metabolites in different mouse brain structures using solid-phase extraction with ultra-high performance liquid chromatography and tandem mass spectrometry with a deuterated internal standard. J. Sep. Sci. 39(11), 2087–2096 (2016).
Medline CASGoogle Scholar
26 Guo C, Shi F, Jiang S et al. Simultaneous identification, confirmation and quantitation of illegal adulterated antidiabetics in herbal medicines and dietary supplements using high-resolution benchtop quadrupole-Orbitrap mass spectrometry. J. Chromatogr. B Analyt. Technol. Biomed. Life Sci. 967, 174–182 (2014).
Medline CASGoogle Scholar

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Financial & competing interests disclosure

This work was supported by the third level in Zhejiang Province ‘151 talents project’; the Public Projects of Zhejiang Province (2015C37064); Medicine and Health Science Fund of Zhejiang Province (2017KY266); Zhejiang Provincial Natural Science Foundation of China (LY16H160035) and Zhejiang Province TCM Science and Technology plan (2016ZB002). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

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The authors state that they have obtained appropriate institutional review board approval or have followed the principles outlined in the Declaration of Helsinki for all human or animal experimental investigations. In addition, for investigations involving human subjects, informed consent has been obtained from the participants involved.

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