A HPLC-UV Method for the Quantification of Regorafenib in Tumor

• Yao Li

  Department of Cell Biology & Institute of Biomedicine, National Engineering Research Center of Genetic Medicine, Guangdong Provincial Key Laboratory of Bioengineering Medicine, College of Life Science and Technology, Jinan University, Guangzhou, Guangdong 510632, China

• Meng-Ning Wei

  Department of Cell Biology & Institute of Biomedicine, National Engineering Research Center of Genetic Medicine, Guangdong Provincial Key Laboratory of Bioengineering Medicine, College of Life Science and Technology, Jinan University, Guangzhou, Guangdong 510632, China

• Wen-Ji Zhang

  Department of Cell Biology & Institute of Biomedicine, National Engineering Research Center of Genetic Medicine, Guangdong Provincial Key Laboratory of Bioengineering Medicine, College of Life Science and Technology, Jinan University, Guangzhou, Guangdong 510632, China

• Zhi Shi

  Department of Cell Biology & Institute of Biomedicine, National Engineering Research Center of Genetic Medicine, Guangdong Provincial Key Laboratory of Bioengineering Medicine, College of Life Science and Technology, Jinan University, Guangzhou, Guangdong 510632, China

Regorafenib has been approved for the treatment of colorectal cancer, gastrointestinal stromal tumor and hepatocellular carcinoma. High-performance liquid chromatography (HPLC) was developed and validated for determination of regorafenib in xenograft tumors. After protein precipitation with acetonitrile, regorafenib were separated using gradient elution (C18 Ultrabase column). Quantification was performed at 262 nm. Calibration curves were linear over the range 48.8-50000 ng/ml. The assay was applied to the determination of the drug in the tumor of nude mice receiving regorafenib 50 mg orally, and could be useful for therapeutic drug monitoring of regorafenib in routine clinical practice.

Wilhelm SM, Dumas J, Adnane L, Lynch M, Carter CA, Schutz G, Thierauch KH and Zopf D. Regorafenib (BAY 73-4506): a new oral multikinase inhibitor of angiogenic, stromal and oncogenic receptor tyrosine kinases with potent preclinical antitumor activity. International journal of cancer Journal international du cancer 2011; 129(1): 245-255. https://doi.org/10.1002/ijc.25864

FDA approves regorafenib (Stivarga) for metastatic colorectal cancer. Oncology 2012; 26(10): 896.

FDA approves regorafenib (Stivarga) for GIST. Oncology 2013; 27(3): 164.

Duffy AG and Greten TF. Liver cancer: Regorafenib as second-line therapy in hepatocellular carcinoma. Nat Rev Gastroenterol Hepatol 2017; 14(3): 141-142. https://doi.org/10.1038/nrgastro.2017.7

Daudigeos-Dubus E, Le Dret L, Lanvers-Kaminsky C, Bawa O, Opolon P, Vievard A, Villa I, Pages M, Bosq J, Vassal G, Zopf D and Geoerger B. Regorafenib: Antitumor Activity upon Mono and Combination Therapy in Preclinical Pediatric Malignancy Models. PloS one 2015; 10(11): e0142612. https://doi.org/10.1371/journal.pone.0142612

D'Alessandro R, Refolo MG, Lippolis C, Giannuzzi G, Carella N, Messa C, Cavallini A and Carr BI. Antagonism of sorafenib and regorafenib actions by platelet factors in hepatocellular carcinoma cell lines. BMC cancer 2014; 14: 351. https://doi.org/10.1186/1471-2407-14-351

Hamed HA, Tavallai S, Grant S, Poklepovic A and Dent P. Sorafenib/regorafenib and lapatinib interact to kill CNS tumor cells. Journal of cellular physiology 2015; 230(1): 131-139. https://doi.org/10.1002/jcp.24689

Schmieder R, Hoffmann J, Becker M, Bhargava A, Muller T, Kahmann N, Ellinghaus P, Adams R, Rosenthal A, Thierauch KH, Scholz A, Wilhelm SM and Zopf D. Regorafenib (BAY 73-4506): antitumor and antimetastatic activities in preclinical models of colorectal cancer. International journal of cancer Journal international du cancer 2014; 135(6): 1487-1496. https://doi.org/10.1002/ijc.28669

Davis SL, Eckhardt SG, Messersmith WA and Jimeno A. The development of regorafenib and its current and potential future role in cancer therapy. Drugs of today 2013; 49(2): 105-115. https://doi.org/10.1358/dot.2013.49.2.1930525

George S, Wang Q, Heinrich MC, Corless CL, Zhu M, Butrynski JE, Morgan JA, Wagner AJ, Choy E, Tap WD, Yap JT, Van den Abbeele AD, Manola JB, Solomon SM, Fletcher JA, von Mehren M, et al. Efficacy and safety of regorafenib in patients with metastatic and/or unresectable GI stromal tumor after failure of imatinib and sunitinib: a multicenter phase II trial. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2012; 30(19): 2401-2407. https://doi.org/10.1200/JCO.2011.39.9394

Zhang YK, Wang YJ, Lei ZN, Zhang GN, Zhang XY, Wang DS, Al-Rihani SB, Shukla S, Ambudkar SV, Kaddoumi A, Shi Z and Chen ZS. Regorafenib antagonizes BCRP-mediated multidrug resistance in colon cancer. Cancer Lett 2019; 442: 104-112. https://doi.org/10.1016/j.canlet.2018.10.032

Wang YJ, Zhang YK, Zhang GN, Al Rihani SB, Wei MN, Gupta P, Zhang XY, Shukla S, Ambudkar SV, Kaddoumi A, Shi Z and Chen ZS. Regorafenib overcomes chemotherapeutic multidrug resistance mediated by ABCB1 transporter in colorectal cancer: In vitro and in vivo study. Cancer Lett 2017; 396: 145-154. https://doi.org/10.1016/j.canlet.2017.03.011

Zhang WJ, Li Y, Wei MN, Chen Y, Qiu JG, Jiang QW, Yang Y, Zheng DW, Qin WM, Huang JR, Wang K, Wang YJ, Yang DH, Chen ZS and Shi Z. Synergistic antitumor activity of regorafenib and lapatinib in preclinical models of human colorectal cancer. Cancer Lett 2017; 386: 100-109. https://doi.org/10.1016/j.canlet.2016.11.011

Xie G, Gong Y, Wu S, Li C, Yu S, Wang Z, Chen J, Zhao Q, Li J and Liang H. Meta-Analysis of Regorafenib-Associated Adverse Events and Their Management in Colorectal and Gastrointestinal Stromal Cancers. Adv Ther 2019; 36(8): 1986-1998. https://doi.org/10.1007/s12325-019-01013-5

Yin X, Yin Y, Shen C, Chen H, Wang J, Cai Z, Chen Z and Zhang B. Adverse events risk associated with regorafenib in the treatment of advanced solid tumors: meta-analysis of randomized controlled trials. Onco Targets Ther 2018; 11: 6405-6414. https://doi.org/10.2147/OTT.S156760

Cao M, Li F, Wang Y and Zhang J. Treatment-related serious adverse events and fatal adverse events with regorafenib in cancer patients: a meta-analysis of phase 3 randomized controlled trials. Invest New Drugs 2017; 35(6): 834-838. https://doi.org/10.1007/s10637-017-0512-6

De Wit M, Boers-Doets CB, Saettini A, Vermeersch K, de Juan CR, Ouwerkerk J, Raynard SS, Bazin A and Cremolini C. Prevention and management of adverse events related to regorafenib. Support Care Cancer 2014; 22(3): 837-846. https://doi.org/10.1007/s00520-013-2085-z

Fujita K, Miura M and Shibata H. Quantitative determination of regorafenib and its two major metabolites in human plasma with high-performance liquid chromatography and ultraviolet detection. Biomed Chromatogr 2016; 30(10): 1611-1617. https://doi.org/10.1002/bmc.3730

Hafner FT, Werner D and Kaiser M. Determination of regorafenib (BAY 73-4506) and its major human metabolites BAY 75-7495 (M-2) and BAY 81-8752 (M-5) in human plasma by stable-isotope dilution liquid chromatography-tandem mass spectrometry. Bioanalysis 2014; 6(14): 1923-1937. https://doi.org/10.4155/bio.14.52

Luethi D, Durmus S, Schinkel AH, Schellens JH, Beijnen JH and Sparidans RW. Liquid chromatography-tandem mass spectrometric assay for the multikinase inhibitor regorafenib in plasma. Biomedical chromatography : BMC 2014; 28(10): 1366-1370. https://doi.org/10.1002/bmc.3176

• PDF