Abstract
Aim:
To investigate the pharmacokinetics of imatinib in Chinese chronic myelogenous leukemia (CML) patients.
Methods:
Fourty-six naïve Chinese CML patients treated with imatinib (400 and 600 mg daily, n=36 and 10, respectively) were recruited. The correlations of imatinib (400 mg) trough plasma concentrations (Cmins) with the patients' characteristics and responses were analyzed.
Results:
The overall mean (±SD, CV%) steady-state Cmins for imatinib at 400 mg (n=36) and 600 mg (n=10) daily was 1325.61 ng/mL (±583.53 ng/mL; 44%) and 1550.90 ng/mL (±462.63 ng/mL; 30%), respectively, and no statistically significant differences were found between them (P=0.267). At 400 mg daily, female patients had significantly higher Cmins than the male patients (P=0.048), and molecular responses were not correlated with imatinib Cmins, but they were correlated with time elapsed before imatinib therapy.
Conclusion:
The results suggest that Chinese CML patients have higher imatinib Cmins than their Caucasian counterparts and that the optimal initial imatinib dose for them requires further investigation.
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References
Melo JV, Deininger MW . Biology of chronic myelogenous leukemia–signaling pathways of initiation and transformation. Hematol Oncol Clin North Am 2004; 18: 545–68.
Lugo TG, Pendergast AM, Muller AJ, Witte ON . Tyrosine kinase activity and transformation potency of bcr-abl oncogene products. Science 1990; 247: 1079–82.
Druker BJ . Translation of the Philadelphia chromosome into therapy for CML. Blood 2008; 112: 4808–17.
Druker BJ, Guilhot F, O'Brien SG, Gathmann I, Kantarjian H, Gattermann N, et al. Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. New Engl J Med 2006; 355: 2408–17.
Apperley JF . Part I: mechanisms of resistance to imatinib in chronic myeloid leukaemia. Lancet Oncol 2007; 8: 1018–29.
Volpe G, Panuzzo C, Ulisciani S, Cilloni D . Imatinib resistance in CML. Cancer Lett 2009; 274: 1–9.
Crossman LC, Druker BJ, Deininger MW, Pirmohamed M, Wang L, Clark RE . hOCT1 and resistance to imatinib. Blood 2005; 106: 1133–4.
White DL, Saunders VA, Dang P, Engler J, Venables A, Zrim S, et al. Most CML patients who have a suboptimal response to imatinib have low OCT-1 activity: higher doses of imatinib may overcome the negative impact of low OCT-1 activity. Blood 2007; 110: 4064–72.
Picard S, Titier K, Etienne G, Teilhet E, Ducint D, Bernard MA, et al. Trough imatinib plasma levels are associated with both cytogenetic and molecular responses to standard-dose imatinib in chronic myeloid leukemia. Blood 2007; 109: 3496–9.
Larson RA, Druker BJ, Guilhot F, O'Brien SG, Riviere GJ, Krahnke T, et al. Imatinib pharmacokinetics and its correlation with response and safety in chronic-phase chronic myeloid leukemia: a subanalysis of the IRIS study. Blood 2008; 111: 4022–8.
Singh N, Kumar L, Meena R, Velpandian T . Drug monitoring of imatinib levels in patients undergoing therapy for chronic myeloid leukaemia: comparing plasma levels of responders and non-responders. Eur J Clin Pharmacol 2009; 65: 545–9.
Forrest DL, Trainor S, Brinkman RR, Barnett MJ, Hogge DE, Nevill TJ, et al. Cytogenetic and molecular responses to standard-dose imatinib in chronic myeloid leukemia are correlated with Sokal risk scores and duration of therapy but not trough imatinib plasma levels. Leuk Res 2009; 33: 271–5.
Sakai M, Miyazaki Y, Matsuo E, Moriuchi Y, Hata T, Fukushima T, et al. Long-term efficacy of imatinib in a practical setting is correlated with imatinib trough concentration that is influenced by body size: a report by the Nagasaki CML Study Group. Int J Hematol 2009; 89: 319–25.
O'Brien SG, Guilhot F, Larson RA, Gathmann I, Baccarani M, Cervantes F, et al. Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med 2003; 348: 994–1004.
Kreuzer KA, Lass U, Bohn A, Landt O, Schmidt CA . LightCycler technology for the quantitation of bcr/abl fusion transcripts. Cancer Res 1999; 59: 3171–4.
Hughes T, Deininger M, Hochhaus A, Branford S, Radich J, Kaeda J, et al. Monitoring CML patients responding to treatment with tyrosine kinase inhibitors: review and recommendations for harmonizing current methodology for detecting BCR-ABL transcripts and kinase domain mutations and for expressing results. Blood 2006; 108: 28–37.
Rousselot P, Huguet F, Rea D, Legros L, Cayuela JM, Maarek O, et al. Imatinib mesylate discontinuation in patients with chronic myelogenous leukemia in complete molecular remission for more than 2 years. Blood 2007; 109: 58–60.
Peng B, Hayes M, Resta D, Racine-Poon A, Druker BJ, Talpaz M, et al. Pharmacokinetics and pharmacodynamics of imatinib in a phase I trial with chronic myeloid leukemia patients. J Clin Oncol 2004; 22: 935–42.
Peng B, Lloyd P, Schran H . Clinical pharmacokinetics of imatinib. Clin Pharmacokinet 2005; 44: 879–94.
Schmidli H, Peng B, Riviere GJ, Capdeville R, Hensley M, Gathmann I, et al. Population pharmacokinetics of imatinib mesylate in patients with chronicphase chronic myeloid leukaemia: results of a phase III study. Br J Clin Pharmacol 2005; 60: 35–44.
Gschwind HP, Pfaar U, Waldmeier F, Zollinger M, Sayer C, Zbinden P, et al. Metabolism and disposition of imatinib mesylate in healthy volunteers. Drug Metab Dispos 2005; 33: 1503–12.
Wang Y, Zhou L, Dutreix C, Leroy E, Yin Q, Sethuraman V, et al. Effects of imatinib (Glivec) on the pharmacokinetics of metoprolol, a CYP2D6 substrate, in Chinese patients with chronic myelogenous leukaemia. Br J Clin Pharmacol 2008; 65: 885–92.
Cortes J, Giles F, O'Brien S, Thomas D, Garcia-Manero G, Rios MB, et al. Result of high-dose imatinib mesylate in patients with Philadelphia chromosome-positive chronic myeloid leukemia after failure of interferon-α. Blood 2003; 102: 83–6.
Kantarjian HM, Talpaz M, O'Brien S, Giles F, Garcia-Manero G, Faderl S, et al. Dose escalation of imatinib mesylate can overcome resistance to standard-dose therapy in patients with chronic myelogenous leukemia. Blood 2003; 101: 473–5.
Kantarjian H, Talpaz M, O'Brien S, Garcia-Manero G, Verstovsek S, Giles F, et al. High-dose imatinib mesylate therapy in newly diagnosed Philadelphia chromosome-positive chronic phase chronic myeloid leukemia. Blood 2004; 103: 2873–8.
Deenik W, van der Holt B, Verhoef GE, Smit WM, Kersten MJ, Kluin-Nelemans HC, et al. Dose finding study of imatinib in combination with intravenous cytarabine: feasibility in newly diagnosed patients with chronic myeloid leukemia. Blood 2008; 111: 2581–8.
Hughes TP, Branford S, White DL, Reynolds J, Koelmeyer R, Seymour JF, et al. Impact of early dose intensity on cytogenetic and molecular responses in chronic-phase CML patients receiving 600 mg/day of imatinib as initial therapy. Blood 2008; 112: 3965–73.
Chen ZC, You Y, Zhu XM, Li QB, Li WM, Zou P . A clinical study of treating 120 cases of adult chronic myelocytic leukemia with imatinib mesylate. Zhonghua Nei Ke Za Zhi 2007; 46: 1003–6.
Morishima Y, Ogura M, Nishimura M, Yazaki F, Bessho M, Mizoguchi H, et al. Efficacy and safety of imatinib mesylate for patients in the first chronic phase of chronic myeloid leukemia: results of a Japanese phase II clinical study. Int J Hematol 2004; 80: 261–6.
Miyazawa K, Nishimaki J, Katagiri T, Sashida G, Shoji N, Kawakubo K, et al. Thrombocytopenia induced by imatinib mesylate (Glivec) in patients with chronic myelogenous leukemia: is 400 mg daily of imatinib mesylate an optimal starting dose for Japanese patients? Int J Hematol 2003; 77: 93–5.
Horikoshi A, Takei K, Sawada S . Effects of lower dose of imatinib to CML patients. Leuk Res 2003; 27: 1167.
Horikoshi A, Takei K, Sawada S . Relationship between the daily dose of imatinib per square meter, and its plasma concentration in patients with chronic-phase chronic myeloid leukemia (CML). Leuk Res 2007; 31: 574–5.
Park SJ, Choi IK, Seo HY, Sung HJ, Park KH, Kim SJ, et al. Reduced dose of imatinib for patients with chronic myeloid leukemia and low body surface area. Acta Haematol 2007; 118: 219–21.
Kobayashi S, Kimura F, Kobayashi A, Sato K, Motoyoshi K . Efficacy of low-dose imatinib in chronic-phase chronic myelogenous leukemia patients. Acta Haematol 2009; 88: 311–5.
Acknowledgements
We thank Qing LI for helping collect patients' disease history, Dr Jian-qiong LIU for guidance with data analysis, and Wuxi PharmaTech for imatinib plasma trough concentration analysis.
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Li, Qb., Chen, C., Chen, Zc. et al. Imatinib plasma trough concentration and its correlation with characteristics and response in Chinese CML patients. Acta Pharmacol Sin 31, 999–1004 (2010). https://doi.org/10.1038/aps.2010.79
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DOI: https://doi.org/10.1038/aps.2010.79
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