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Current Pharmaceutical Analysis

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ISSN (Print): 1573-4129
ISSN (Online): 1875-676X

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General Research Article

A Validated 2D-LC-UV Method for Simultaneous Determination of Imatinib and N-desmethylimatinib in Plasma and its Clinical Application for Therapeutic Drug Monitoring with GIST Patients

Author(s): Houli Li, Di Zhang, Xiaoliang Cheng, Qiaowei Zheng, Kai Cheng, Lilong Xiong*, Maoyi Wang, Weihua Dong and Weiyi Feng*

Volume 18, Issue 1, 2022

Published on: 24 November, 2020

Page: [122 - 131] Pages: 10

DOI: 10.2174/1573412917999201124143834

Abstract

Background: The trough concentration (Cmin) of Imatinib (IM) is closely related to the treatment outcomes and adverse reactions of patients with gastrointestinal stromal tumors (GIST). However, the drug plasma level has great inter- and intra-individual variability, and therapeutic drug monitoring (TDM) is highly recommended.

Objective: To develop a novel, simple, and economical two-dimensional liquid chromatography method with the ultraviolet detector (2D-LC-UV) for simultaneous determination of IM and its major active metabolite, N-desmethyl imatinib (NDIM) in human plasma, and then apply the method for TDM of the drug.

Methods: The sample was processed by simple protein precipitation. Two target analytes were separated on the one-dimension column, captured on the middle column, and then transferred to the two-dimension column for further analysis. The detection was performed at 264 nm. The column temperature was maintained at 40˚C and the injection volume was 500 μL. Totally 32 plasma samples were obtained from patients with GIST who were receiving IM.

Results: IM and NDIM were separated well from other impurities and the entire analytical time for each run was 12.0 min. The calibration curves had good linearity in the range of 33.5-2678.4 ng/mL for IM, and 20.0-1600.0 ng/mL for NDIM, respectively. The extraction efficiency was more than 95%. The acceptable accuracy, precision, recovery and stability were also obtained. The Cmin of the drug in patients was measured with the validated method.

Conclusion: The novel 2D-LC-UV method is simple, stable, highly automated and independent of specialized technicians, which greatly increases the real-time capability of routine TDM for IM in hospital.

Keywords: Imatinib, N-demethylimatinib, 2D-LC-UV, therapeutic drug monitoring, plasma, gastrointestinal stromal tumors.

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[1]
Gronchi, A.; Blay, J.Y.; Trent, J.C. The role of high-dose imatinib in the management of patients with gastrointestinal stromal tumor. Cancer, 2010, 116(8), 1847-1858.
[http://dx.doi.org/10.1002/cncr.24944] [PMID: 20166214]
[2]
Gopie, P.; Mei, L.; Faber, A.C.; Grossman, S.R.; Smith, S.C.; Boikos, S.A. Classification of gastrointestinal stromal tumor syndromes. Endocr. Relat. Cancer, 2018, 25(2), R49-R58.
[http://dx.doi.org/10.1530/ERC-17-0329] [PMID: 29170162]
[3]
Nishida, T.; Blay, J.Y.; Hirota, S.; Kitagawa, Y.; Kang, Y.K. The standard diagnosis, treatment, and follow-up of gastrointestinal stromal tumors based on guidelines. Gastric Cancer, 2016, 19(1), 3-14.
[http://dx.doi.org/10.1007/s10120-015-0526-8] [PMID: 26276366]
[4]
Casali, P.G.; Abecassis, N.; Bauer, S.; Biagini, R.; Bielack, S.; Bonvalot, S.; Boukovinas, I.; Bovee, J.V.M.G.; Brodowicz, T.; Broto, J.M.; Buonadonna, A.; De Alava, E.; Dei Tos, A.P.; Del Muro, X.G.; Dileo, P.; Eriksson, M.; Fedenko, A.; Ferraresi, V.; Ferrari, A.; Ferrari, S.; Frezza, A.M.; Gasperoni, S.; Gelderblom, H.; Gil, T.; Grignani, G.; Gronchi, A.; Haas, R.L.; Hannu, A.; Hassan, B.; Hohenberger, P.; Issels, R.; Joensuu, H.; Jones, R.L.; Judson, I.; Jutte, P.; Kaal, S.; Kasper, B.; Kopeckova, K.; Krakorova, D.A.; Le Cesne, A.; Lugowska, I.; Merimsky, O.; Montemurro, M.; Pantaleo, M.A.; Piana, R.; Picci, P.; Piperno-Neumann, S.; Pousa, A.L.; Reichardt, P.; Robinson, M.H.; Rutkowski, P.; Safwat, A.A.; Schoffski, P.; Sleijfer, S.; Stacchiotti, S.; Hall, K.S.; Unk, M.; Van Coevorden, F.; Van der Graaf, W.; Whelan, J.; Wardelmann, E.; Zaikova, O.; Blay, J.Y.; EURACAN, E. G. C. Gastrointestinal stromal tumours: ESMO-EURACAN Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann. Oncol., 2018, 29, 68-78.
[http://dx.doi.org/10.1093/annonc/mdy095]
[5]
Turjap, M.; Jurica, J.; Demlova, R. Potential clinical benefit of therapeutic drug monitoring of imatinib in oncology Klinicka onkologie: casopis Ceske a Slovenske onkologicke spolecnosti, 2015, 28(2), 105-111.
[6]
Güller, U.; Tarantino, I.; Cerny, T.; Schmied, B.M.; Warschkow, R. Population-based SEER trend analysis of overall and cancer-specific survival in 5138 patients with gastrointestinal stromal tumor. BMC Cancer, 2015, 15, 557.
[http://dx.doi.org/10.1186/s12885-015-1554-9] [PMID: 26223313]
[7]
Blanke, C.D.; Demetri, G.D.; von Mehren, M.; Heinrich, M.C.; Eisenberg, B.; Fletcher, J.A.; Corless, C.L.; Fletcher, C.D.; Roberts, P.J.; Heinz, D.; Wehre, E.; Nikolova, Z.; Joensuu, H. Long-term results from a randomized phase II trial of standard- versus higher-dose imatinib mesylate for patients with unresectable or metastatic gastrointestinal stromal tumors expressing KIT. J. Clin. Oncol., 2008, 26(4), 620-625.
[http://dx.doi.org/10.1200/JCO.2007.13.4403] [PMID: 18235121]
[8]
Peng, B.; Lloyd, P.; Schran, H. Clinical pharmacokinetics of imatinib. Clin. Pharmacokinet., 2005, 44(9), 879-894.
[http://dx.doi.org/10.2165/00003088-200544090-00001] [PMID: 16122278]
[9]
Widmer, N.; Decosterd, L.A.; Leyvraz, S.; Duchosal, M.A.; Rosselet, A.; Debiec-Rychter, M.; Csajka, C.; Biollaz, J.; Buclin, T. Relationship of imatinib-free plasma levels and target genotype with efficacy and tolerability. Br. J. Cancer, 2008, 98(10), 1633-1640.
[http://dx.doi.org/10.1038/sj.bjc.6604355] [PMID: 18475296]
[10]
Demetri, G.D.; Wang, Y.; Wehrle, E.; Racine, A.; Nikolova, Z.; Blanke, C.D.; Joensuu, H.; von Mehren, M. Imatinib plasma levels are correlated with clinical benefit in patients with unresectable/metastatic gastrointestinal stromal tumors. J. Clin. Oncol., 2009, 27(19), 3141-3147.
[http://dx.doi.org/10.1200/JCO.2008.20.4818] [PMID: 19451435]
[11]
Lankheet, N.A.G.; Desar, I.M.E.; Mulder, S.F.; Burger, D.M.; Kweekel, D.M.; van Herpen, C.M.L.; van der Graaf, W.T.A.; van Erp, N.P. Optimizing the dose in cancer patients treated with imatinib, sunitinib and pazopanib. Br. J. Clin. Pharmacol., 2017, 83(10), 2195-2204.
[http://dx.doi.org/10.1111/bcp.13327] [PMID: 28500677]
[12]
Farag, S.; Verheijen, R.B.; Martijn Kerst, J.; Cats, A.; Huitema, A.D.R.; Steeghs, N. Imatinib pharmacokinetics in a large observational cohort of gastrointestinal stromal tumour patients. Clin. Pharmacokinet., 2017, 56(3), 287-292.
[http://dx.doi.org/10.1007/s40262-016-0439-7] [PMID: 27435281]
[13]
Eechoute, K.; Fransson, M.N.; Reyners, A.K.; de Jong, F.A.; Sparreboom, A.; van der Graaf, W.T.A.; Friberg, L.E.; Schiavon, G.; Wiemer, E.A.; Verweij, J.; Loos, W.J.; Mathijssen, R.H.; De Giorgi, U. A long-term prospective population pharmacokinetic study on imatinib plasma concentrations in GIST patients. Clin. Cancer Res., 2012, 18(20), 5780-5787.
[http://dx.doi.org/10.1158/1078-0432.CCR-12-0490] [PMID: 22850565]
[14]
Bouchet, S.; Poulette, S.; Titier, K.; Moore, N.; Lassalle, R.; Abouelfath, A.; Italiano, A.; Chevreau, C.; Bompas, E.; Collard, O.; Duffaud, F.; Rios, M.; Cupissol, D.; Adenis, A.; Ray-Coquard, I.; Bouché, O.; Le Cesne, A.; Bui, B.; Blay, J-Y.; Molimard, M. Relationship between imatinib trough concentration and outcomes in the treatment of advanced gastrointestinal stromal tumours in a real-life setting. Eur. J. Cancer, 2016, 57, 31-38.
[http://dx.doi.org/10.1016/j.ejca.2015.12.029] [PMID: 26851399]
[15]
Ijzerman, N. S.; Groenland, S. L.; Koenen, A. M.; Kerst, M.; van der Graaf, W. T. A.; Rosing, H.; Beijnen, J. H.; Huitema, A. D. R.; Steeghs, N. Therapeutic drug monitoring of imatinib in patients with gastrointestinal stromal tumours - Results from daily clinical practice European journal of cancer (Oxford, England : 1990), 2020, 136, 140-148.
[16]
Josephs, D.H.; Fisher, D.S.; Spicer, J.; Flanagan, R.J. Clinical pharmacokinetics of tyrosine kinase inhibitors: implications for therapeutic drug monitoring. Ther. Drug Monit., 2013, 35(5), 562-587.
[http://dx.doi.org/10.1097/FTD.0b013e318292b931] [PMID: 24052062]
[17]
Murray, M.; Gillani, T.B.; Ghassabian, S.; Edwards, R.J.; Rawling, T. Differential effects of hepatic cirrhosis on the intrinsic clearances of sorafenib and imatinib by CYPs in human liver. Eur. J. Pharm. Sci., 2018, 114, 55-63.
[http://dx.doi.org/10.1016/j.ejps.2017.12.003] [PMID: 29223619]
[18]
Tan, K.L.; Ankathil, R.; Gan, S.H. Method development and validation for the simultaneous determination of imatinib mesylate and N-desmethyl imatinib using rapid resolution high performance liquid chromatography coupled with UV-detection. J. Chromatogr. B Analyt. Technol. Biomed. Life Sci., 2011, 879(30), 3583-3591.
[http://dx.doi.org/10.1016/j.jchromb.2011.09.048] [PMID: 22000961]
[19]
Golabchifar, A-A.; Rouini, M-R.; Shafaghi, B.; Rezaee, S.; Foroumadi, A.; Khoshayand, M-R. Optimization of the simultaneous determination of imatinib and its major metabolite, CGP74588, in human plasma by a rapid HPLC method using D-optimal experimental design. Talanta, 2011, 85(5), 2320-2329.
[http://dx.doi.org/10.1016/j.talanta.2011.07.093] [PMID: 21962649]
[20]
Luo, X.; Huang, L.; Li, T.; Xue, X.; Wang, Y.; Chen, Y.; Yang, C.; Feng, W. Simultaneous determination of concentrations of imatinib and N-desmethyl imatinib in human plasma by HPLC. Zhongguo Xin Yao Zazhi, 2018, 27(10), 1159-1164.
[21]
Lin, J.; Ying, N.; Wu, Y.; Lin, G. Determination of imatinib and CGP74588 in rat plasma by HPLC and its application to a pharmacokinetic study. Curr. Pharm. Anal., 2018, 14(2), 133-138.
[http://dx.doi.org/10.2174/1573412913666161121105119]
[22]
Miura, M.; Takahashi, N. Routine therapeutic drug monitoring of tyrosine kinase inhibitors by HPLC-UV or LC-MS/MS methods. Drug Metab. Pharmacokinet., 2016, 31(1), 12-20.
[http://dx.doi.org/10.1016/j.dmpk.2015.09.002] [PMID: 26732608]
[23]
Ubhayasekera, S.J.K.A.; Aluthgedara, W.; Ek, B.; Bergquist, J. Simultaneous quantification of imatinib and CGP74588 in human plasma by liquid chromatography-time of flight mass spectrometry (LC-TOF-MS). Anal. Methods, 2016, 8(15), 3046-3054.
[http://dx.doi.org/10.1039/C5AY02807H]
[24]
Parise, R.A.; Ramanathan, R.K.; Hayes, M.J.; Egorin, M.J. Liquid chromatographic-mass spectrometric assay for quantitation of imatinib and its main metabolite (CGP 74588) in plasma. J. Chromatogr. B Analyt. Technol. Biomed. Life Sci., 2003, 791(1-2), 39-44.
[http://dx.doi.org/10.1016/S1570-0232(03)00206-X] [PMID: 12798163]
[25]
Solassol, I.; Bressolle, F.; Philibert, L.; Charasson, V.; Astre, C.; Pinguet, F. Liquid chromatography-electrospray mass spectrometry determination of imatinib and its main metabolite, N-desmethy-imatinib in human plasma. J. Liq. Chromatogr. Relat. Technol., 2006, 29(20), 2957-2974.
[http://dx.doi.org/10.1080/10826070600981058]
[26]
Zhuang, W.; Qiu, H-B.; Chen, X-M.; Yuan, X-H.; Yang, L-F.; Sun, X-W.; Zhou, X-J.; Huang, M.; Wang, X-D.; Zhou, Z-W. Simultaneous quantification of imatinib and its main metabolite N-demethyl-imatinib in human plasma by liquid chromatography-tandem mass spectrometry and its application to therapeutic drug monitoring in patients with gastrointestinal stromal tumor. Biomed. Chromatogr., 2017, 31(12)
[http://dx.doi.org/10.1002/bmc.4022] [PMID: 28621487]
[27]
Ostrowicz, A.; Mikołajczak, P.L.; Wierzbicka, M.; Boguradzki, P. Bioequivalence study of 400 and 100 mg imatinib film-coated tablets in healthy volunteers. Acta Pol. Pharm., 2014, 71(5), 843-854.
[PMID: 25362813]
[28]
Bakhtiar, R.; Lohne, J.; Ramos, L.; Khemani, L.; Hayes, M.; Tse, F. High-throughput quantification of the anti-leukemia drug STI571 (Gleevec) and its main metabolite (CGP 74588) in human plasma using liquid chromatography-tandem mass spectrometry. J. Chromatogr. B Analyt. Technol. Biomed. Life Sci., 2002, 768(2), 325-340.
[http://dx.doi.org/10.1016/S1570-0232(01)00611-0] [PMID: 11888061]
[29]
Rochat, B.; Fayet, A.; Widmer, N.; Lahrichi, S.L.; Pesse, B.; Décosterd, L.A.; Biollaz, J. Imatinib metabolite profiling in parallel to imatinib quantification in plasma of treated patients using liquid chromatography-mass spectrometry. J. Mass Spectrom., 2008, 43(6), 736-752.
[http://dx.doi.org/10.1002/jms.1369] [PMID: 18286663]
[30]
Iacuzzi, V.; Posocco, B.; Zanchetta, M.; Montico, M.; Marangon, E.; Poetto, A.S.; Buzzo, M.; Gagno, S.; Buonadonna, A.; Guardascione, M.; Casetta, B.; Toffoli, G. Development and validation of LC-MS/MS method for imatinib and norimatinib monitoring by finger-prick DBS in gastrointestinal stromal tumor patients. PLoS One, 2019, 14(11)
[http://dx.doi.org/10.1371/journal.pone.0225225] [PMID: 31743371]
[31]
Rao, Z.; Li, B-x.; Jin, Y-w.; Wen, K.; Ma, Y-r.; Zhang, G-q.; Zhang, F.; Zhou, Y.; Wu, X-a. Simultaneous Determination of Imatinib and N-Desmethyl Imatinib in Rat Plasma and Tissues Using LC-MS/MS. Curr. Pharm. Anal., 2019, 15(2), 121-129.
[http://dx.doi.org/10.2174/1573412913666170821124952]
[32]
Liu, W.; Jin, X.; Yao, S.; Wang, F. Determination of risperidone and 9-hydroxyrisperidone in human serum by heart-cutting isocratic two-dimensional liquid chromatography. Anal. Lett., 2020, 53(12), 2002-2019.
[http://dx.doi.org/10.1080/00032719.2020.1728291]
[33]
Yu, Y.; Shi, J.; Wang, F.; Tang, X.H.; Liu, Y.G. Quantification of the plasma concentration of apatinib by 2-dimensional liquid chromatography. Ther. Drug Monit., 2019, 41(4), 489-496.
[http://dx.doi.org/10.1097/FTD.0000000000000609] [PMID: 31083044]
[34]
Sheng, Y.; Zhou, B. High-throughput determination of vancomycin in human plasma by a cost-effective system of two-dimensional liquid chromatography. J. Chromatogr. A, 2017, 1499, 48-56.
[http://dx.doi.org/10.1016/j.chroma.2017.02.061] [PMID: 28420531]
[35]
Liu, W.; Shang, X.; Yao, S.; Wang, F. A novel and nonderivatization method for the determination of valproic acid in human serum by two-dimensional liquid chromatography. Biomed. Chromatogr., 2020, 34(1)
[http://dx.doi.org/10.1002/bmc.4695] [PMID: 31469425]
[36]
Li, X.; Wang, F.; Xu, B.; Yu, X.; Yang, Y.; Zhang, L.; Li, H. Determination of the free and total concentrations of vancomycin by two-dimensional liquid chromatography and its application in elderly patients. J. Chromatogr. B Analyt. Technol. Biomed. Life Sci., 2014, 969, 181-189.
[http://dx.doi.org/10.1016/j.jchromb.2014.08.002] [PMID: 25178192]
[37]
Filgueira, M.R.; Huang, Y.; Witt, K.; Castells, C.; Carr, P.W. Improving peak capacity in fast online comprehensive two-dimensional liquid chromatography with post-first-dimension flow splitting. Anal. Chem., 2011, 83(24), 9531-9539.
[http://dx.doi.org/10.1021/ac202317m] [PMID: 22017622]
[38]
Pirok, B.W.J.; Gargano, A.F.G.; Schoenmakers, P.J. Optimizing separations in online comprehensive two-dimensional liquid chromatography. J. Sep. Sci., 2018, 41(1), 68-98.
[http://dx.doi.org/10.1002/jssc.201700863] [PMID: 29027363]
[39]
Dugo, P.; Favoino, O.; Luppino, R.; Dugo, G.; Mondello, L. Comprehensive two-dimensional normal-phase (adsorption)-reversed-phase liquid chromatography. Anal. Chem., 2004, 76(9), 2525-2530.
[http://dx.doi.org/10.1021/ac0352981] [PMID: 15117193]
[40]
Croom, K.F.; Perry, C.M. Imatinib mesylate: in the treatment of gastrointestinal stromal tumours. Drugs, 2003, 63(5), 513-522.
[http://dx.doi.org/10.2165/00003495-200363050-00005] [PMID: 12600228]
[41]
Delbaldo, C.; Chatelut, E.; Ré, M.; Deroussent, A.; Séronie-Vivien, S.; Jambu, A.; Berthaud, P.; Le Cesne, A.; Blay, J-Y.; Vassal, G. Pharmacokinetic-pharmacodynamic relationships of imatinib and its main metabolite in patients with advanced gastrointestinal stromal tumors. Clin. Cancer Res., 2006, 12(20 Pt 1), 6073-6078.
[http://dx.doi.org/10.1158/1078-0432.CCR-05-2596] [PMID: 17062683]
[42]
van Erp, N.P.; Gelderblom, H.; Karlsson, M.O.; Li, J.; Zhao, M.; Ouwerkerk, J.; Nortier, J.W.; Guchelaar, H.J.; Baker, S.D.; Sparreboom, A. Influence of CYP3A4 inhibition on the steady-state pharmacokinetics of imatinib. Clin. Cancer Res., 2007, 13(24), 7394-7400.
[http://dx.doi.org/10.1158/1078-0432.CCR-07-0346] [PMID: 18094422]
[43]
Dematteo, R.P.; Ballman, K.V.; Antonescu, C.R.; Maki, R.G.; Pisters, P.W.T.; Demetri, G.D.; Blackstein, M.E.; Blanke, C.D.; von Mehren, M.; Brennan, M.F.; Patel, S.; McCarter, M.D.; Polikoff, J.A.; Tan, B.R.; Owzar, K.; Stud, A.I.A.G. American College of Surgeons Oncology Group (ACOSOG) Intergroup Adjuvant GIST Study Team. Adjuvant imatinib mesylate after resection of localised, primary gastrointestinal stromal tumour: a randomised, double-blind, placebo-controlled trial. Lancet, 2009, 373(9669), 1097-1104.
[http://dx.doi.org/10.1016/S0140-6736(09)60500-6] [PMID: 19303137]
[44]
Qian, Y.; Sun, L-N.; Liu, Y-J.; Zhang, Q.; Xu, J-H.; Ma, Z-Q.; Zhang, X-H.; Xu, H.; Wang, Y-Q. Genetic polymorphisms and adverse events on unbound imatinib and its active metabolite concentration in patients with gastrointestinal stromal tumors. Front. Pharmacol., 2019, 10, 854.
[http://dx.doi.org/10.3389/fphar.2019.00854] [PMID: 31417408]
[45]
Widmer, N.; Decosterd, L.A.; Csajka, C.; Leyvraz, S.; Duchosal, M.A.; Rosselet, A.; Rochat, B.; Eap, C.B.; Henry, H.; Biollaz, J.; Buclin, T. Population pharmacokinetics of imatinib and the role of alpha-acid glycoprotein. Br. J. Clin. Pharmacol., 2006, 62(1), 97-112.
[http://dx.doi.org/10.1111/j.1365-2125.2006.02719.x] [PMID: 16842382]
[46]
Li, D.; Dück, R.; Schmitz, O.J. The advantage of mixed-mode separation in the first dimension of comprehensive two-dimensional liquid-chromatography. J. Chromatogr. A, 2014, 1358, 128-135.
[http://dx.doi.org/10.1016/j.chroma.2014.06.086] [PMID: 25042443]
[47]
Iguiniz, M.; Heinisch, S. Two-dimensional liquid chromatography in pharmaceutical analysis. Instrumental aspects, trends and applications. J. Pharm. Biomed. Anal., 2017, 145, 482-503.
[http://dx.doi.org/10.1016/j.jpba.2017.07.009] [PMID: 28746908]

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