Development and validation of an HPLC-UV method for routine trough plasma concentration monitoring of imatinib in Chinese patients with gastrointestinal stromal tumor

doi:10.5246/jcps.2020.09.059

Abstract

Abstract:

Imatinib is the first-line medication for the treatment of advanced gastrointestinal stromal tumor (GIST). Due to the large inter-individual variability, it is recommended to monitor the trough plasma concentration of imatinib to ensure the efficacy and safety of imatinib therapy. In the present study, an HPLC-UV method was developed and validated for quantitating imatinib in the plasma of Chinese GIST patients. The samples were processed by protein precipitation and then mixed with a neutralizing agent (1.4 g K₂CO₃ and 0.65 g KCl dissolved in 5 mL ultrapure water). The chromatographic separation was performed on an InertSustain C₁₈ column (250 mm×4.6 mm, 5 µM) maintained at 40 ºC utilizing the mobile phase consisted of 25 mM NH₄H₂PO₄ (pH 8.0)–acetonitrile (61:39, v/v) at a flow rate of 1 mL/min, with an ultraviolet detector set at 265 nm. The method was fully validated according to the published guidelines. The plotted calibration curves were all linear within the range of 50 to 10 000 ng/mL. The validation results of the intra-day and inter-day accuracies and precisions ranged from –5.81% to 6.33%. The extraction recoveries were within the range of 92.38% to 97.86%. All the results of stability studies were all consistent with the acceptance criteria of within ±15%. Finally, the method was successfully applied to trough plasma concentration monitoring of imatinib in 150 Chinese GIST patients orally administrated with imatinib. Incurred sample reanalysis was conducted, results of which were also in accordance with the acceptance criteria of within ±20%.

Key words: Imatinib, HPLC, Gastrointestinal stromal tumor, Therapeutic drug monitoring, Incurred sample reanalysis

CLC Number:

R917

Supporting:

Yi Zhou, Junli Lai, Feng Qiu, Jun Zhang. Development and validation of an HPLC-UV method for routine trough plasma concentration monitoring of imatinib in Chinese patients with gastrointestinal stromal tumor[J]. Journal of Chinese Pharmaceutical Sciences, 2020, 29(9): 637-648.

References

[1] 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, 6073-6078.

[2] Demetri, G.D.; Wang, Y.F.; 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, 3141-3147.

[3] Tap, W.D.; Schwartz, G.K. That‟s the “GIST” of it: use of adjuvant imatinib after resection of a primary GI stromal tumor. J. Clin. Oncol. 2014, 32, 1543-1546.

[4] Widmer, N.; Bardin, C.; Chatelut, E.; Paci, A.; Beijnen, J.; Levêque, D.; Veal, G.; Astier, A. Review of therapeutic drug monitoring of anticancer drugs part two-Targeted therapies. Eur. J. Cancer. 2014, 50, 2020-2036.

[5] von Mehren, M.; Widmer, N. Correlations between imatinib pharmacokinetics, pharmacodynamics, adherence, and clinical response in advanced metastatic gastrointestinal stromal tumor (GIST): an emerging role for drug blood level testing? Cancer Treat. Rev. 2011, 37, 291-299.

[6] Bardin, C.; Veal, G.; Paci, A.; Chatelut, E.; Astier, A.; Levêque, D.; Widmer, N.; Beijnen, J. Therapeutic drug monitoring in cancer-Are we missing a trick? Eur. J. Cancer. 2014, 50, 2005-2009.

[7] Gotta, V.; Widmer, N.; Decosterd, L.A.; Chalandon, Y.; Heim, D.; Gregor, M.; Benz, R.; Leoncini-Franscini, L.; Baerlocher, G.M.; Duchosal, M.A.; Csajka, C.; Buclin, T. Clinical usefulness of therapeutic concentration monitoring for imatinib dosage individualization: results from a randomized controlled trial. Cancer Chemother. Pharmacol. 2014, 74, 1307-1319.

[8] Judson, I. Therapeutic drug monitoring of imatinib: new data strengthen the case. Clin. Cancer Res. 2012, 18, 5517-5519.

[9] Gastrointestinal stromal tumours: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann. Oncol. 2014, 25, iii21-iii26.

[10] Hochhaus, A.; Dreyling, M. Chronic myelogenous leukemia: ESMO clinical recommendations for the diagnosis, treatment and follow-up. Ann. Oncol. 2008, 19, ii63-ii64.

[11] von Mehren, M.; Randall, R.L.; Benjamin, R.S.; Boles, S.; Bui, M.M.; Casper, E.S.; Conrad, E.U. III, DeLaney, T.F.; Ganjoo, K.N.; George, S.; Gonzalez, R.J.; Heslin, M.J.; Kane, J.M. III, Mayerson, J.; McGarry, S.V.; Meyer, C.; O‟Donnell, R.J.; Pappo, A.S.; Paz, I.B.; Pfeifer, J.D.; Riedel, R.F.; Schuetze, S.; Schupak, K.D.; Schwartz, H.S.; van Tine, B.A.; Wayne, J.D.; Bergman, M.A.; Sundar, H. Gastrointestinal stromal tumors. J. Natl. Compr. Cancer Netw. 2014, 12, 853-862.

[12] Yoon, S.; Ryu, M.H.; Yoo, C.; Beck, M.Y.; Ryoo, B.Y.; Kang, Y.K. Imatinib plasma monitoring-guided dose modification for managing imatinib-related toxicities in gastrointestinal stromal tumor patients. J. Korean Med. Sci. 2013, 28, 1248-1252.

[13] Lankheet, N.A.G.; Knapen, L.M.; Schellens, J.H.M.; Beijnen, J.H.; Steeghs, N.; Huitema, A.D.R. Plasma concentrations of tyrosine kinase inhibitors imatinib, erlotinib, and sunitinib in routine clinical outpatient cancer care. Ther. Drug Monit. 2014, 36, 326-334.

[14] 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, 12-20.

[15] Davies, A.; Hayes, A.K.; Knight, K.; Watmough, S.J.; Pirmohamed, M.; Clark, R.E. Simultaneous determination of nilotinib, imatinib and its main metabolite (CGP-74588) in human plasma by ultra-violet high performance liquid chromatography. Leuk. Res. 2010, 34, 702-707.

[16] Widmer, N.; Béguin, A.; Rochat, B.; Buclin, T.; Kovacsovics, T.; Duchosal, M.A.; Leyvraz, S.; Rosselet, A.; Biollaz, J.; Decosterd, L.A. Determination of imatinib (Gleevec®) in human plasma by solid-phase extraction-liquid chromatography-ultraviolet absorbance detection. J. Chromatogr. B. 2004, 803, 285-292.

[17] Bende, G.; Kollipara, S.; Movva, S.; Moorthy, G.; Saha, R. Validation of an HPLC method for determination of imatinib mesylate in rat serum and its application in a pharmacokinetic study. J. Chromatogr. Sci. 2010, 48, 334-341.

[18] Awidi, A.; Salem, I.I.; Najib, N.; Mefleh, R.; Tarawneh, B. Determination of imatinib plasma levels in patients with chronic myeloid leukemia by high performance liquid chromatography-ultraviolet detection and liquid chromatography-tandem mass spectrometry: Methods‟ comparison. Leuk. Res. 2010, 34, 714-717.

[19] Miura, M.; Takahashi, N.; Sawada, K.I. Quantitative determination of imatinib in human plasma with high-performance liquid chromatography and ultraviolet detection. J. Chromatogr. Sci. 2011, 49, 412-415.

[20] 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, 2320-2329.

[21] Pirro, E.; de Francia, S.; de Martino, F.; Racca, S.; di Carlo, F.; Fava, C.; Ulisciani, S.; Rege Cambrin, G.; Saglio, G. A new HPLC-UV validated method for therapeutic drug monitoring of tyrosine kinase inhibitors in leukemic patients. J. Chromatogr. Sci. 2011, 49, 753-757.

[22] Miura, M.; Takahashi, N.; Sawada, K.I. Quantitative determination of imatinib in human plasma with high-performance liquid chromatography and ultraviolet detection. J. Chromatogr. Sci. 2011, 49, 412-415.

[23] 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. 2011, 879, 3583-3591.

[24] Alkharfy, K.M.; Khan, R.M.A.; Al-Asmari, M.; Alhadeyah, B.H.; Ahmad, A. Quantitative determination of imatinib stability under various stress conditions. J. Pharm. Bioallied Sci. 2013, 5, 49-52.

[25] Birch, M.; Morgan, P.E.; Handley, S.; Ho, A.; Ireland, R.; Flanagan, R.J. Simple methodology for the therapeutic drug monitoring of the tyrosine kinase inhibitors dasatinib and imatinib. Biomed. Chromatogr. 2013, 27, 335-342.

[26] Kaza, M.; Piorkowska, E.; Filist, M.; Rudzki, P.J. Hplc-uv assay of imatinib in human plasma optimized for bioequivalence studies. Acta Pol. Pharm. 2016, 73, 1495-1503.

[27] Velpandian, T.; Mathur, R.; Agarwal, N.K.; Arora, B.; Kumar, L.; Gupta, S.K. Development and validation of a simple liquid chromatographic method with ultraviolet detection for the determination of imatinib in biological samples. J. Chromatogr. B. 2004, 804, 431-434.

[28] Schleyer, E.; Pursche, S.; Köhne, C.H.; Schuler, U.; Renner, U.; Gschaidmeier, H.; Freiberg-Richter, J.; Leopold, T.; Jenke, A.; Bonin, M.; Bergemann, T.; le Coutre, P.; Gruner, M.; Bornhäuser, M.; Ottmann, O.G.; Ehninger, G. Liquid chromatographic method for detection and quantitation of STI-571 and its main metabolite N-desmethyl-STI in plasma, urine, cerebrospinal fluid, culture medium and cell preparations. J. Chromatogr. B. 2004, 799, 23-36.

[29] Roth, O.; Spreux-Varoquaux, O.; Bouchet, S.; Rousselot, P.; Castaigne, S.; Rigaudeau, S.; Raggueneau, V.; Therond, P.; Devillier, P.; Molimard, M.; Maneglier, B. Imatinib assay by HPLC with photodiode-array UV detection in plasma from patients with chronic myeloid leukemia: Comparison with LC-MS/MS. Clin. Chimica Acta. 2010, 411, 140-146.

[30] Bioanalytical Method Validation. Guidance for Industry. U.S. Food and Drug Administration. 2018, 1-41. https://www.fda.gov/media/70858/download.

[31] Guideline on bioanalytical method validation. Eur. Med. Agency. 2012, 1-23. https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-bioanalytical-method-validation_en.pdf.

[32] Wang, Y.F.; Chia, Y.L.; Nedelman, J.; Schran, H.; Mahon, F.; Molimard, M. A therapeutic drug monitoring algorithm for refining the imatinib trough level obtained at different sampling times. Ther. Drug Monit. 2009, 31, 579-584.

[33] Ramazani, F.; Chen, W.; van Nostrum, C.F.; Storm, G.; Kiessling, F.; Lammers, T.; Hennink, W.E.; Kok, R.J. Formulation and characterization of microspheres loaded with imatinib for sustained delivery. Int. J. Pharm. 2015, 482, 123-130.

[34] Yadav, M.; Shrivastav, P.S. Incurred sample reanalysis (ISR): a decisive tool in bioanalytical research. Bioanalysis. 2011, 3, 1007-1024.

[35] Teng, J.F.T.; Mabasa, V.H.; Ensom, M.H.H. The role of therapeutic drug monitoring of imatinib in patients with chronic myeloid leukemia and metastatic or unresectable gastrointestinal stromal tumors. Ther. Drug Monit. 2012, 34, 85-97.