Monitoring of plasma concentration of imatinib in patients with gastrointestinal stromal tumors and its significance_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

YIN Yuan ¹ , XIANG Jin ² , SHEN Chaoyong ¹ , TANG Sumin ¹ ,  ZHANG Bo ¹

1. Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu 610041, P.R.China;
2. Laboratory of Clinical Pharmacology, West China Hospital, Sichuan University, Chengdu 610041, P.R.China;

Corresponding?author：

ZHANG Bo, Email: zhangbo7310@126.com

Keywords：

gastrointestinal stromal tumor; imatinib; imatinib concentration; side effect

DOI：

10.7507/1007-9424.201701052

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Objective To describe pharmacokinetic of imatinib in a cohort of gastrointestinal stromal tumor (GIST) patients in routine clinical care from West China Hospital of Sichuan University. Methods The imatinib trough concentration (C_min) in 42 patients with GIST who were taking imatinib in routine clinical care setting in West China Hospital from 2010 to 2016 was measured. The clinical features and follow-up data were collected. Results The mean imatinib C_min in 42 patients was 1 757 μg/L (199–7 435 μg/L), 10 of 42 patients presented with C_min values was lower than 1 000 μg/L. The imatinib C_min of 18 patients received an imatinib dose of 300 mg/d or 24 patients treated with 400 mg/d imatinib was (1 313±479) μg/L and (1 775±1 520) μg/L, respectively (P=0.222), but the rate of low C_min (lower than 1 000 μg/L) in the two different dose groups had no significant difference (P=0.347). In Cox regression, no statistically significant association between the low C_min and the time to progression of GIST could be demonstrated 〔HR=0.171, 95%CI：(0.106, 12.990),P=0.898〕. Conclusion The preliminary results of limited cases in this study show that some GIST patients are systematically underexposed in routine clinical care, an individualized treatment based on monitoring of imatinib C_min is likely to be more efficient than a fixed-dose treatment.

Citation： YINYuan, XIANGJin, SHENChaoyong, TANGSumin, ZHANGBo. Monitoring of plasma concentration of imatinib in patients with gastrointestinal stromal tumors and its significance. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2017, 24(2): 158-162. doi: 10.7507/1007-9424.201701052 Copy

1.	Gronchi A, Blay JY, Trent JC. The role of high-dose imatinib in the management of patients with gastrointestinal stromal tumor. Cancer, 2010, 116(8): 1847-1858.
2.	楊顯金, 陳佳慧, 杜江, 等. 胃腸道間質瘤的診治現狀與進展. 中國普外基礎與臨床雜志, 2014, 21(8): 1040-1045.
3.	Eechoute K, Fransson MN, Reyners AK, et al. A long-term prospective population pharmacokinetic study on imatinib plasma concentrations in GIST patients. Clin Cancer Res, 2012, 18(20): 5780-5787.
4.	Demetri GD, Wang Y, Wehrle E, et al. Imatinib plasma levels are correlated with clinical benefit in patients with unresectable/ metastatic gastrointestinal stromal tumors. J Clin Oncol, 2009, 27(19): 3141-3147.
5.	Choi H. Response evaluation of gastrointestinal stromal tumors. Oncologist, 2008, 13 Suppl 2: 4-7.
6.	Bakhtiar R, Lohne J, Ramos L, et al. 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.
7.	Demetri GD, von Mehren M, Blanke CD, et al. Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. N Engl J Med, 2002, 347(7): 472-480.
8.	Verweij J, Casali PG, Zalcberg J, et al. Progression-free survival in gastrointestinal stromal tumours with high-dose imatinib: randomised trial. Lancet, 2004, 364(9440): 1127-1134.
9.	Blanke CD, Rankin C, Demetri GD, et al. Phase Ⅲ randomized, intergroup trial assessing imatinib mesylate at two dose levels in patients with unresectable or metastatic gastrointestinal stromal tumors expressing the kit receptor tyrosine kinase: S0033. J Clin Oncol, 2008, 26(4): 626-632.
10.	孫乃萍, 李健, 高靜, 等. 胃腸間質瘤患者中Imatinib血藥濃度與治療療效的相關性. 基礎醫學與臨床, 2010, 30(12): 1329-1333.
11.	Faber E, Divoká M, Skoumalová I, et al. A lower dosage of imatinib is sufficient to maintain undetectable disease in patients with chronic myeloid leukemia with long-term low-grade toxicity of the treatment. Leuk Lymphoma, 2015: 1-6.[Epub ahead of print].
12.	Farag S, Verheijen RB, Martijn Kerst J, et al. Imatinib pharmacokinetics in a large observational cohort of gastrointestinal stromal tumour patients. Clin Pharmacokinet, 2016 Jul 19.[Epub ahead of print].
13.	Yoo C, Ryu MH, Ryoo BY, et al. Changes in imatinib plasma trough level during long-term treatment of patients with advanced gastrointestinal stromal tumors: correlation between changes in covariates and imatinib exposure. Invest New Drugs, 2012, 30(4): 1703-1708.
14.	Yoo C, Ryu MH, Kang BW, et al. Cross-sectional study of imatinib plasma trough levels in patients with advanced gastrointestinal stromal tumors: impact of gastrointestinal resection on exposure to imatinib. J Clin Oncol, 2010, 28(9): 1554-1559.
15.	National Comprehensive Cancer Network (NCCN). National Comprehensive Cancer Network Soft tissue sarcoma (version 1. 2015). 2015, Aug 20. Available at: http://www.nccn.org/professionals/physician_gls/pdf/sarcoma.pdf.
16.	Jang BH, Kim BW, Lim KJ, et al. A case of disseminated intra-abdominal gastrointestinal stromal tumor managed with low dose imatinib. Korean J Gastroenterol, 2015, 65(6): 366-369.
17.	Yin Y, Xiang J, Tang S, et al. A lower dosage of imatinib in patients with gastrointestinal stromal tumors with toxicity of the treatment. Medicine (Baltimore), 2016, 95(49): e5488.

1. Gronchi A, Blay JY, Trent JC. The role of high-dose imatinib in the management of patients with gastrointestinal stromal tumor. Cancer, 2010, 116(8): 1847-1858.
2. 楊顯金, 陳佳慧, 杜江, 等. 胃腸道間質瘤的診治現狀與進展. 中國普外基礎與臨床雜志, 2014, 21(8): 1040-1045.
3. Eechoute K, Fransson MN, Reyners AK, et al. A long-term prospective population pharmacokinetic study on imatinib plasma concentrations in GIST patients. Clin Cancer Res, 2012, 18(20): 5780-5787.
4. Demetri GD, Wang Y, Wehrle E, et al. Imatinib plasma levels are correlated with clinical benefit in patients with unresectable/ metastatic gastrointestinal stromal tumors. J Clin Oncol, 2009, 27(19): 3141-3147.
5. Choi H. Response evaluation of gastrointestinal stromal tumors. Oncologist, 2008, 13 Suppl 2: 4-7.
6. Bakhtiar R, Lohne J, Ramos L, et al. 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.
7. Demetri GD, von Mehren M, Blanke CD, et al. Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. N Engl J Med, 2002, 347(7): 472-480.
8. Verweij J, Casali PG, Zalcberg J, et al. Progression-free survival in gastrointestinal stromal tumours with high-dose imatinib: randomised trial. Lancet, 2004, 364(9440): 1127-1134.
9. Blanke CD, Rankin C, Demetri GD, et al. Phase Ⅲ randomized, intergroup trial assessing imatinib mesylate at two dose levels in patients with unresectable or metastatic gastrointestinal stromal tumors expressing the kit receptor tyrosine kinase: S0033. J Clin Oncol, 2008, 26(4): 626-632.
10. 孫乃萍, 李健, 高靜, 等. 胃腸間質瘤患者中Imatinib血藥濃度與治療療效的相關性. 基礎醫學與臨床, 2010, 30(12): 1329-1333.
11. Faber E, Divoká M, Skoumalová I, et al. A lower dosage of imatinib is sufficient to maintain undetectable disease in patients with chronic myeloid leukemia with long-term low-grade toxicity of the treatment. Leuk Lymphoma, 2015: 1-6.[Epub ahead of print].
12. Farag S, Verheijen RB, Martijn Kerst J, et al. Imatinib pharmacokinetics in a large observational cohort of gastrointestinal stromal tumour patients. Clin Pharmacokinet, 2016 Jul 19.[Epub ahead of print].
13. Yoo C, Ryu MH, Ryoo BY, et al. Changes in imatinib plasma trough level during long-term treatment of patients with advanced gastrointestinal stromal tumors: correlation between changes in covariates and imatinib exposure. Invest New Drugs, 2012, 30(4): 1703-1708.
14. Yoo C, Ryu MH, Kang BW, et al. Cross-sectional study of imatinib plasma trough levels in patients with advanced gastrointestinal stromal tumors: impact of gastrointestinal resection on exposure to imatinib. J Clin Oncol, 2010, 28(9): 1554-1559.
15. National Comprehensive Cancer Network (NCCN). National Comprehensive Cancer Network Soft tissue sarcoma (version 1. 2015). 2015, Aug 20. Available at: http://www.nccn.org/professionals/physician_gls/pdf/sarcoma.pdf.
16. Jang BH, Kim BW, Lim KJ, et al. A case of disseminated intra-abdominal gastrointestinal stromal tumor managed with low dose imatinib. Korean J Gastroenterol, 2015, 65(6): 366-369.
17. Yin Y, Xiang J, Tang S, et al. A lower dosage of imatinib in patients with gastrointestinal stromal tumors with toxicity of the treatment. Medicine (Baltimore), 2016, 95(49): e5488.

CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Monitoring of plasma concentration of imatinib in patients with gastrointestinal stromal tumors and its significance

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