Abstract
Purpose
Imatinib mesylate is used as first line therapy in the treatment of chronic myeloid leukaemia. This study was designed to study the correlation of plasma levels of imatinib with response to the therapy.
Methods
A total of 40 chronic myeloid leukaemia patients in the chronic phase of the disease were recruited and placed into two groups of 20 patients: imatinib responders and imatinib non-responders, respectively. Each blood sample was taken 24 h after and immediately prior to taking a 400 mg oral dose of imatinib. Drug levels were detected by high-performance liquid chromatography.
Results
The mean plasma imatinib levels in the imatinib non-responders were significantly lower than those in the imatinib responders (0.70 vs. 2.34 µM, respectively; p = 0.002).
Conclusions
Plasma levels of imatinib were correlated with response to the therapy, so routine monitoring of the therapeutic levels of the drug should be carried out specifically in treatment-resistant cases for determining dose escalation.
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References
Sawyers CL (1999) Chronic myeloid leukemia. N Engl J Med 340:1330–1340
Kumar L (2006) Chronic myelogenous leukemia (CML): an update. Nat Med J India 19:255–263
Peggs K, Mackinnon S (2003) Imatinib mesylate—the new gold standard for treatment of chronic myeloid leukemia. N Engl J Med 348:1048–1050
Gambacorti-Passerini CB, Gunby RH, Kaeda J (2003) Molecular mechanisms of resistance to imatinib in Philadelphia chromosome-positive leukaemias. Lancet Oncol 4:75–85
Druker BJ, Tamura S, Buchdunger E (1996) Effects of a selective inhibitors of the Abl tyrosinekinase on the growth of BCR–ABL positive cells. Nat Med 2:561–566
Cancer Care Ontario (2008) Revised Drug formulary. Available via DIALOG: http://www.cancercare.on.ca/pdfdrugs/Imatinib—Mesylate.pdf Accessed 12 Aug 2008
le Coutre P, O’Dwyer ME, Druker BJ (2004) Pharmacokinetics and cellular uptake of imatinib and its main metabolite CGP74588. Cancer Chemother Pharmacol 53:313–323
Larson RA, Druker BJ, Guilhot F (2008) Imatinib pharmacokinetics and its correlation with response and safety in chronic phase chronic myeloid leukemia: a subanalysis of the IRIS study. Blood 111:4022–4028
Velpandian T, Kumar L, Arora B (2004) Development and validation of a simple liquid chromatographic method with ultraviolet detection for the determination of imatinb in biological samples. J Chromatogr B 804:431–434
Peng B, Lloyd P, Schran H (2005) Clinical pharmacokinetics of imatinib. Clin Pharmacokinet 44:879–894
Picard S, Titier K, Etienne G (2007) Trough imatinib plasma levels are associated with both cytogenetic and molecular responses for standard dose imatinib in chronic myeloid leukemia. Blood 109:3496–3499
Branford S, Rudzki Z, Walsh S (2003) Detection of BCR–ABL mutations in patients with CML treated with imatinib is virtually always accompanied by clinical resistance and mutations in the ATP phosphate-binding loop (P-loop) are associated with poor prognosis. Blood 102:276–283
Jabbour E, Kantarjian H, Jones D (2006) Frequency and clinical significance of BCR–ABL mutations in patients with chronic myeloid leukaemia treated with imatinib mesylate. Leukemia 20:1767–1773
Wilkinson GR (1996) Cytochrome P4503A (CYP3A) metabolism: prediction of in vivo activity in humans. J Pharmacokinet Biopharm 24:475–490
Wojnowski L (2004) Genetics of the variable expression of CYP3A in humans. Ther Drug Monit 26:192–199
Illmer T, Schaich M, Platzbecker (2004) P-glycoprotein-mediated drug efflux is a resistance mechanism of chronic myelogenous leukaemia cells to treatment with imatinib mesylate. Leukemia 18:401–408
Thomas J, Wang L, Clark RE (2004) Active transport of imatinib into and out of cells: implications for drug resistance. Blood 104:3739–3745
Wei Y, Hardling M, Olsson B (2006) Not all imatinib resistance in CML are BCR–ABL kinase domain mutations. J Clin Pharm 85:841–847
Rais N, Chawla YK, Kohli KK (2006) CYP3A phenotypes and genotypes in north indians. Eur J Clin Pharm 62:417–422
Lamba V, Lamba JK, Dilawari JB (1988) Genetic polymorphism of CYP2D6 in North Indian subjects. Eur J Clin Pharm 54:9–11
Crossman LC, Druker BJ, Deininger MWN (2005) HOCT1 and resistance to imatinib. Blood 106:1133–1134
Kantarjian HM, Talpaz M, OBrien S (2008) Dose escalation of imatinib mesylate can overcome resistance to standard-dose therapy in patients with CML. Blood 101:473–475
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We thank Dr. Alok K Ravi for helping us in with the HPLC operations
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Singh, N., Kumar, L., Meena, R. et al. 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 65, 545–549 (2009). https://doi.org/10.1007/s00228-009-0621-z
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DOI: https://doi.org/10.1007/s00228-009-0621-z