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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

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Summary

A pharmacokinetic study in patients with gastrointestinal stromal tumors (GIST) suggested that imatinib plasma concentration may decrease following long-term exposure. We assessed changes in imatinib plasma trough levels (Cmin) during long-term treatment. Follow-up (FU) imatinib Cmin was measured in 65 patients who received the same dose of imatinib for at least 9 months after previous (initial) tests. After exclusion of 7 patients who had been treated with imatinib for over 2 years at the time of initial testing, 58 patients were included in this analysis. The median intervals from initiation of imatinib to initial testing and from initial to FU testing were 5.5 months (range, 0.5–24.0 months) and 13.0 months (range, 9.6–17.9 months), respectively. Mean inter- and intra-subject variability values were 47.7% and 20.9%, respectively, at initial measurements, and 45.2% and 19.4%, respectively, at FU. Mean FU imatinib Cmin (1,370 ± 661 ng/mL) was significantly higher than mean initial Cmin (1,171 ± 573 ng/mL; p = 0.003). Compared with initial Cmin, FU Cmin was decreased in 22 patients and increased in 36, with median changes of 13% and 32%, respectively. Multivariate analysis showed a significant correlation between the ratio of FU to initial imatinib Cmin and that of albumin (r = −0.39, p = 0.003). During long-term treatment, imatinib Cmin did not decrease significantly but remained stable or increased in most patients. Changes in imatinib Cmin were associated with changes in albumin concentration. Monitoring of imatinib Cmin only for concerns about time-dependent increases in imatinib clearance is not necessary.

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References

  1. Heinrich MC, Griffith DJ, Druker BJ, Wait CL, Ott KA, Zigler AJ (2000) Inhibition of c-kit receptor tyrosine kinase activity by STI 571, a selective tyrosine kinase inhibitor. Blood 96(3):925–932

    CAS  PubMed  Google Scholar 

  2. Buchdunger E, Cioffi CL, Law N, Stover D, Ohno-Jones S, Druker BJ et al (2000) Abl protein-tyrosine kinase inhibitor STI571 inhibits in vitro signal transduction mediated by c-kit and platelet-derived growth factor receptors. J Pharmacol Exp Ther 295(1):139–145

    CAS  PubMed  Google Scholar 

  3. Day E, Waters B, Spiegel K, Alnadaf T, Manley PW, Buchdunger E et al (2008) Inhibition of collagen-induced discoidin domain receptor 1 and 2 activation by imatinib, nilotinib and dasatinib. Eur J Pharmacol 599(1–3):44–53

    Article  CAS  PubMed  Google Scholar 

  4. Demetri GD, von Mehren M, Blanke CD, Van den Abbeele AD, Eisenberg B, Roberts PJ et al (2002) Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. N Engl J Med 347(7):472–480

    Article  CAS  PubMed  Google Scholar 

  5. Verweij J, Casali PG, Zalcberg J, LeCesne A, Reichardt P, Blay JY et al (2004) Progression-free survival in gastrointestinal stromal tumours with high-dose imatinib: randomised trial. Lancet 364(9440):1127–1134

    Article  CAS  PubMed  Google Scholar 

  6. Blanke CD, Rankin C, Demetri GD, Ryan CW, von Mehren M, Benjamin RS et al (2008) 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 26(4):626–632

    Article  CAS  PubMed  Google Scholar 

  7. Ryu MH, Kang WK, Bang YJ, Lee KH, Shin DB, Ryoo BY et al (2009) A prospective, multicenter, phase 2 study of imatinib mesylate in Korean patients with metastatic or unresectable gastrointestinal stromal tumor. Oncology 76(5):326–332

    Article  CAS  PubMed  Google Scholar 

  8. Blanke CD, Demetri GD, von Mehren M, Heinrich MC, Eisenberg B, Fletcher JA et al (2008) 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 26(4):620–625

    Article  CAS  PubMed  Google Scholar 

  9. Debiec-Rychter M, Sciot R, Le Cesne A, Schlemmer M, Hohenberger P, van Oosterom AT et al (2006) KIT mutations and dose selection for imatinib in patients with advanced gastrointestinal stromal tumours. Eur J Cancer 42(8):1093–1103

    Article  CAS  PubMed  Google Scholar 

  10. Park I, Ryu MH, Sym SJ, Lee SS, Jang G, Kim TW et al (2009) Dose escalation of imatinib after failure of standard dose in Korean patients with metastatic or unresectable gastrointestinal stromal tumor. Jpn J Clin Oncol 39(2):105–110

    Article  PubMed  Google Scholar 

  11. Peng B, Lloyd P, Schran H (2005) Clinical pharmacokinetics of imatinib. Clin Pharmacokinet 44(9):879–894

    Article  CAS  PubMed  Google Scholar 

  12. Judson I, Ma P, Peng B, Verweij J, Racine A, di Paola ED et al (2005) Imatinib pharmacokinetics in patients with gastrointestinal stromal tumour: a retrospective population pharmacokinetic study over time. EORTC Soft Tissue and Bone Sarcoma Group. Cancer Chemother Pharmacol 55(4):379–386. doi:10.1007/s00280-004-0876-0

    Article  CAS  PubMed  Google Scholar 

  13. Delbaldo C, Chatelut E, Re M, Deroussent A, Seronie-Vivien S, Jambu A et al (2006) Pharmacokinetic-pharmacodynamic relationships of imatinib and its main metabolite in patients with advanced gastrointestinal stromal tumors. Clin Cancer Res 12(20 Pt 1):6073–6078

    Article  CAS  PubMed  Google Scholar 

  14. Menon-Andersen D, Mondick JT, Jayaraman B, Thompson PA, Blaney SM, Bernstein M et al (2009) Population pharmacokinetics of imatinib mesylate and its metabolite in children and young adults. Cancer Chemother Pharmacol 63(2):229–238. doi:10.1007/s00280-008-0730-x

    Article  CAS  PubMed  Google Scholar 

  15. Schmidli H, Peng B, Riviere GJ, Capdeville R, Hensley M, Gathmann I et al (2005) Population pharmacokinetics of imatinib mesylate in patients with chronic-phase chronic myeloid leukaemia: results of a phase III study. Br J Clin Pharmacol 60(1):35–44

    Article  CAS  PubMed  Google Scholar 

  16. Yoo C, Ryu MH, Kang BW, Yoon SK, Ryoo BY, Chang HM et al (2010) 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 28(9):1554–1559

    Article  CAS  PubMed  Google Scholar 

  17. Widmer N, Decosterd LA, Csajka C, Leyvraz S, Duchosal MA, Rosselet A et al (2006) Population pharmacokinetics of imatinib and the role of alpha-acid glycoprotein. Br J Clin Pharmacol 62(1):97–112

    Article  CAS  PubMed  Google Scholar 

  18. Larson RA, Druker BJ, Guilhot F, O’Brien SG, Riviere GJ, Krahnke T et al (2008) Imatinib pharmacokinetics and its correlation with response and safety in chronic-phase chronic myeloid leukemia: a subanalysis of the IRIS study. Blood 111(8):4022–4028

    Article  CAS  PubMed  Google Scholar 

  19. Picard S, Titier K, Etienne G, Teilhet E, Ducint D, Bernard MA et al (2007) Trough imatinib plasma levels are associated with both cytogenetic and molecular responses to standard-dose imatinib in chronic myeloid leukemia. Blood 109(8):3496–3499

    Article  CAS  PubMed  Google Scholar 

  20. Demetri GD, Wang Y, Wehrle E, Racine A, Nikolova Z, Blanke CD et al (2009) Imatinib plasma levels are correlated with clinical benefit in patients with unresectable/metastatic gastrointestinal stromal tumors. J Clin Oncol 27(19):3141–3147

    Google Scholar 

  21. Cockcroft DW, Gault MH (1976) Prediction of creatinine clearance from serum creatinine. Nephron 16(1):31–41

    Article  CAS  PubMed  Google Scholar 

  22. Bakhtiar R, Lohne J, Ramos L, Khemani L, Hayes M, Tse F (2002) 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 768(2):325–340

    Article  CAS  PubMed  Google Scholar 

  23. Wardelmann E, Merkelbach-Bruse S, Pauls K, Thomas N, Schildhaus HU, Heinicke T et al (2006) Polyclonal evolution of multiple secondary KIT mutations in gastrointestinal stromal tumors under treatment with imatinib mesylate. Clin Cancer Res 12(6):1743–1749

    Article  CAS  PubMed  Google Scholar 

  24. Antonescu CR, Besmer P, Guo T, Arkun K, Hom G, Koryotowski B et al (2005) Acquired resistance to imatinib in gastrointestinal stromal tumor occurs through secondary gene mutation. Clin Cancer Res 11(11):4182–4190

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

We thank Yanfeng Wang, Ph.D. (Novartis Pharmaceuticals), for his valuable advice on the content of this study.

Conflicts of interest

Yoon-Koo Kang: Honorarium and consultant for Novartis and Pfizer

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Authors and Affiliations

  1. Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, 86 Asanbyeongwon-gil, Songpa-gu, Seoul, 138-736, Korea

    Changhoon Yoo, Min-Hee Ryu, Baek-Yeol Ryoo, Mo Youl Beck, Heung-Moon Chang, Jae-Lyun Lee, Tae Won Kim & Yoon-Koo Kang

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  1. Changhoon Yoo
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  2. Min-Hee Ryu
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  3. Baek-Yeol Ryoo
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Correspondence to Yoon-Koo Kang.

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Changhoon Yoo and Min-Hee Ryu contributed equally as the first author

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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 30, 1703–1708 (2012). https://doi.org/10.1007/s10637-011-9633-5

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  • DOI: https://doi.org/10.1007/s10637-011-9633-5

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