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Pharmacokinetic/pharmacodynamic correlation and blood-level testing in imatinib therapy for chronic myeloid leukemia

Leukemia volume 23, pages 1537–1544 (2009)Cite this article

Abstract

Imatinib is the current standard of care in the treatment of chronic myeloid leukemia (CML), inducing durable responses and prolonged progression-free survival. However, plasma exposure to the drug from a given dosing regimen can vary widely among patients. Reasons for this may include incomplete adherence, intrinsic variations in the metabolism of imatinib, and drug–drug interactions. Data from two recent studies have shown a correlation between imatinib trough plasma concentration and clinical response, leading to suggestions that maintaining imatinib blood concentrations above ∼1000 ng/ml might be associated with improved outcomes. In patients who do not respond as well as expected to initial imatinib treatment, measurement of trough plasma concentration could assist with decisions about whether to increase the dose. Blood-level testing may also be helpful in other clinical scenarios: for example, when poor adherence is suspected, adverse reactions are unusually severe, or there is a possible drug–drug interaction. Further work is required to confirm prospectively the link between imatinib plasma concentrations and response, and to define effective trough concentrations in different patient populations. However, based on the current data, imatinib blood-level testing seems to be a useful aid when making clinical decisions in CML.

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References

  1. Goldman JM, Melo JV . Chronic myeloid leukemia—advances in biology and new approaches to treatment. New Engl J Med 2003; 349: 1451–1464.

    Article  CAS  Google Scholar 

  2. Sawyers CL . Chronic myeloid leukemia. N Engl J Med 1999; 340: 1330–1340.

    Article  CAS  Google Scholar 

  3. O'Dwyer M . Multifaceted approach to the treatment of bcr-abl positive leukemias. Oncologist 2002; 7: 30–38.

    Article  CAS  Google Scholar 

  4. Melo JV, Barnes DJ . Chronic myeloid leukaemia as a model of disease evolution in human cancer. Nat Rev Cancer 2007; 7: 441–453.

    Article  CAS  Google Scholar 

  5. Buchdunger E, Cioffi CL, Law N, Stover D, Ohno-Jones S, Druker BJ et al. 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 2000; 295: 139–145.

    CAS  PubMed  Google Scholar 

  6. Okuda K, Weisberg E, Gilliland DG, Griffin JD . ARG tyrosine kinase activity is inhibited by STI571. Blood 2001; 97: 2440–2448.

    Article  CAS  Google Scholar 

  7. Mol CD, Dougan DR, Schneider TR, Skene RJ, Kraus ML, Scheibe DN et al. Structural basis for the autoinhibition and STI571 inhibition of c-Kit tyrosine kinase. J Biol Chem 2004; 279: 31655–31663.

    Article  CAS  Google Scholar 

  8. Dewar AL, Cambareri AC, Zannettino AC, Miller BL, Doherty KV, Hughes TP et al. Macrophage colony-stimulating factor receptor c-fms is a novel target of imatinib. Blood 2005; 105: 3127–3132.

    Article  CAS  Google Scholar 

  9. Baccarani M, Saglio G, Goldman J, Hochhaus A, Simonsson B, Appelbaum F et al. Evolving concepts in the management of chronic myeloid leukemia. Recommendations from an expert panel on behalf of the European LeukemiaNet. Blood 2006; 108: 1809–1820.

    Article  CAS  Google Scholar 

  10. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology. Chronic Myelogenous Leukemia, v.2.2009. National Comprehensive Cancer Network: Jenkintown PA, 2008.

  11. Hochhaus A, O'Brien SG, Guilhot F, Druker BJ, Branford S, Foroni L et al. Six-year follow-up of patients receiving imatinib for the first-line treatment of chronic myeloid leukemia. Leukemia 2009; (E-pub ahead of print).

  12. Gorre ME, Mohammed M, Ellwood K, Hsu N, Paquette R, Rao PN et al. Clinical resistance to STI-571 cancer therapy caused by BCR-ABL gene mutation or amplification. Science 2001; 293: 876–880.

    Article  CAS  Google Scholar 

  13. Radich JP, Dai H, Mao M, Oehler V, Schelter J, Druker B et al. Gene expression changes associated with progression and response in chronic myeloid leukemia. Proc Natl Acad Sci USA 2006; 103: 2794–2799.

    Article  CAS  Google Scholar 

  14. Crossman LC, O'Brien SG . Imatinib therapy in chronic myeloid leukemia. Hematol Oncol Clin North Am 2004; 18: 605–617.

    Article  Google Scholar 

  15. 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: 4022–4028.

    Article  CAS  Google Scholar 

  16. 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: 3496–3499.

    Article  CAS  Google Scholar 

  17. Peng BM, 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: 935–942.

    Article  CAS  Google Scholar 

  18. Peng B, Lloyd P, Schran H . Clinical pharmacokinetics of imatinib. Clin Pharmacokinet 2005; 444: 879–894.

    Article  Google Scholar 

  19. Gambacorti-Passerini C, Zucchetti M, Russo D, Frapolli R, Verga M, Bungaro S et al. Alpha1 acid glycoprotein binds to imatinib (STI571) and substantially alters its pharmacokinetics in chronic myeloid leukemia patients. Clin Cancer Res 2003; 9: 625–632.

    CAS  PubMed  Google Scholar 

  20. O'Brien SG, Meinhardt P, Bond E, Beck J, Peng B, Dutreix C et al. Effects of imatinib mesylate (STI571, Glivec) on the pharmacokinetics of simvastatin, a cytochrome p450 3A4 substrate, in patients with chronic myeloid leukaemia. Br J Cancer 2003; 89: 1855–1859.

    Article  CAS  Google Scholar 

  21. Bolton AE, Peng B, Hubert M, Krebs-Brown A, Capdeville R, Keller U et al. Effect of rifampicin on the pharmacokinetics of imatinib mesylate (Gleevec, STI571) in healthy subjects. Cancer Chemother Pharmacol 2004; 53: 102–106.

    Article  CAS  Google Scholar 

  22. Dutreix C, Peng B, Mehring G, Hayes M, Capdeville R, Pokorny R et al. Pharmacokinetic interaction between ketaconazole and imatinib mesylate (Glivec) in healthy subjects. Cancer Chemother Pharmacol 2004; 54: 290–294.

    Article  CAS  Google Scholar 

  23. Beumer JH, Natale JJ, Lagattuta TF, Raptis A, Egorin MJ . Disposition of imatinib and its metabolite CGP74588 in a patient with chronic myelogenous leukemia and short-bowel syndrome. Pharmacotherapy 2006; 26: 903–907.

    Article  Google Scholar 

  24. Partridge AH, Avorn J, Wang PS, Winer E . Adherence to therapy with oral antineoplastic agents. J Natl Cancer Inst 2002; 94: 652–661.

    Article  Google Scholar 

  25. Osterberg L, Blaschke T . Adherence to medication. N Engl J Med 2005; 353: 487–497.

    Article  CAS  Google Scholar 

  26. Levine AM, Richardson JL, Marks G, Chan K, Graham J, Selser JN et al. Compliance with oral drug therapy in patients with hematologic malignancy. J Clin Oncol 1987; 5: 1469–1476.

    Article  CAS  Google Scholar 

  27. Dagher R, Cohen M, Williams G, Rothmann M, Gobburu J, Robbie G et al. Approval summary of imatinib mesylate in the treatment of metastatic and/or unresectable malignant gastrointestinal stromal tumors. Clin Cancer Res 2002; 8: 3034–3038.

    CAS  PubMed  Google Scholar 

  28. Cohen MH, Williams G, Johnson JR, Duan J, Gobburu J, Rahman A et al. Approval summary for imatinib mesylate capsules in the treatment of chronic myelogenous leukemia. Clin Cancer Res 2002; 8: 935–942.

    CAS  PubMed  Google Scholar 

  29. Wilkinson GR . Cytochrome P4503A (CYP3A) metabolism: prediction of in vivo activity in humans. J Pharmacokinet Biopharm 1996; 24: 475–490.

    Article  CAS  Google Scholar 

  30. Smith P, Bullock JM, Booker BM, Haas CE, Berenson CS, Jusko WJ . The influence of St John's wort on the pharmacokinetics and protein binding of imatinib mesylate. Pharmacotherapy 2004; 24: 1508–1514.

    Article  CAS  Google Scholar 

  31. Frye RF, Fitzgerald SM, Lagatutta TF, Hruska MW, Egorin MJ . Effect of St John's Wort on imatinib mesylate pharmacokinetics. Clin Pharmacol Ther 2004; 76: 323–329.

    Article  CAS  Google Scholar 

  32. Gambacorti-Passerini C, Barni R, le Coutre P, Zucchetti M, Cabrita G, Cleris L et al. Role of α1 acid glycoprotein in the in vivo resistance of human BCR-ABL+ leukemic cells to the Abl inhibitor STI571. J Natl Cancer Inst 2000; 92: 1641–1650.

    Article  CAS  Google Scholar 

  33. Widmer N, Decosterd LA, Leyvraz S, Duchosal MA, Rosselet A, Debiec-Rychter M et al. Relationship of imatinib-free plasma levels and target genotype with efficacy and tolerability. Br J Cancer 2008; 98: 1633–1640.

    Article  CAS  Google Scholar 

  34. Blasdel C, Egorin MJ, Lagattuta TF, Druker BJ, Deininger MW . Therapeutic drug monitoring in CML patients on imatinib. Blood 2007; 110: 1699–1701.

    Article  CAS  Google Scholar 

  35. Bakhtiar R, Lohne J, Ramos L, Khemani L, Hayes M, Tse F . 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 Chromatog B Analyt Technol Biomed Life Sci 2002; 768: 325–340.

    Article  CAS  Google Scholar 

  36. Titier K, Picard S, Ducint D, Teilhet E, Moore N, Berthaud P et al. Quantification of imatinib in human plasma by high performance liquid chromatography-tandem mass spectrometry. Ther Drug Monit 2005; 27: 634–640.

    Article  CAS  Google Scholar 

  37. Pursche S, Ottmann OG, Ehninger G, Schleyer E . High-performance liquid chromatography method with ultraviolet detection for the quantification of the BCR-ABL inhibitor nilotinib (AMN107) in plasma, urine, culture medium and cell preparations. J Chromatogr B Analyt Technol Biomed Life Sci 2007; 852: 208–216.

    Article  CAS  Google Scholar 

  38. Hegedus T, Orfi L, Seprodi A, Váradi A, Sarkadi B, Kéri G . Interaction of tyrosine kinase inhibitors with the human multidrug transporter proteins, MDR1 and MRP1. Biochim Biophys Acta 2002; 1587: 318–325.

    Article  CAS  Google Scholar 

  39. Dai H, Marbach P, Lemaire M, Hayes M, Elmquist WF . Distribution of STI-571 to the brain is limited by P-glycoprotein-mediated efflux. J Pharmacol Exp Ther 2003; 304: 1085–1092.

    Article  CAS  Google Scholar 

  40. Hamada A, Miyano H, Watanabe H, Saito H . Interaction of imatinib mesilate with human P-glycoprotein. J Pharmacol Exp Ther 2003; 307: 824–828.

    Article  CAS  Google Scholar 

  41. Burger H, van Tol H, Boersma AW, Brok M, Wiemer EA, Stoter G et al. Imatinib mesylate (STI571) is a substrate for the breast cancer resistance protein (BCRP)/ABCG2 drug pump. Blood 2004; 104: 2940–2942.

    Article  CAS  Google Scholar 

  42. Ozvegy-Laczka C, Hegedus T, Várady G, Ujhelly O, Schuetz JD, Váradi A et al. High-affinity interaction of tyrosine kinase inhibitors with the ABCG2 multidrug transporter. Mol Pharmacol 2004; 65: 1485–1495.

    Article  Google Scholar 

  43. Breedveld P, Pluim D, Cipriani G, Wielinga P, van Tellingen O, Schinkel AH et al. The effect of Bcrp1 (Abcg2) on the in vivo pharmacokinetics and brain penetration of imatinib mesylate (Gleevec): implications for the use of breast cancer resistance protein and P-glycoprotein inhibitors to enable the brain penetration of imatinib in patients. Cancer Res 2005; 65: 2577–2582.

    Article  CAS  Google Scholar 

  44. Mahon F-X, Deininger MW, Schultheis B, Chabrol J, Reiffers J, Goldman JM et al. Selection and characterization of BCR-ABL positive cell lines with differential sensitivity to the tyrosine kinase inhibitor STI571: diverse mechanisms of resistance. Blood 2000; 96: 1070–1079.

    CAS  PubMed  Google Scholar 

  45. Mahon F-X, Belloc F, Lagarde V, Chollet C, Moreau-Gaudry F, Reiffers J et al. MDR1 gene overexpression confers resistance to imatinib mesylate in leukemia cell line models. Blood 2003; 101: 2368–2373.

    Article  CAS  Google Scholar 

  46. Thomas J, Wang L, Clark RE, Pirmohamed M . Active transport of imatinib into and out of cells: implications for drug resistance. Blood 2004; 104: 3739–3745.

    Article  CAS  Google Scholar 

  47. Dulucq S, Bouchet S, Turcq B, Lippert E, Etienne G, Reiffers J et al. Multidrug resistance gene (MDR1) polymorphisms are associated with major molecular responses to standard-dose imatinib in chronic myeloid leukemia. Blood 2008; 112: 2024–2027.

    Article  CAS  Google Scholar 

  48. White DL, Saunders VA, Dang P, Engler J, Zannettino AC, Cambareri AC et al. OCT-1-mediated influx is a key determinant of the intracellular uptake of imatinib but not nilotinib (AMN107): reduced OCT-1 activity is the cause of low in vitro sensitivity to imatinib. Blood 2006; 108: 697–704.

    Article  CAS  Google Scholar 

  49. Crossman L, Druker B, Deininger M, Pirmohamed M, Wang L, Clark RE . hOCT 1 and resistance to imatinib. Blood 2005; 106: 1133–1134.

    Article  CAS  Google Scholar 

  50. Wang L, Giannoudis A, Lane S, Williamson P, Pirmohamed M, Clark RE . Expression of the uptake drug transporter hOCT1 is an important clinical determinant of the response to imatinib in chronic myeloid leukemia. Clin Pharmacol Ther 2008; 83: 258–264.

    Article  CAS  Google Scholar 

  51. 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: 4064–4072.

    Article  CAS  Google Scholar 

  52. 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: 2873–2878.

    Article  CAS  Google Scholar 

  53. Kantarjian H, 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: 473–475.

    Article  CAS  Google Scholar 

  54. Jabbour E, Kantarjian HM, Jones D, Shan J, O'Brien S, Reddy N et al. Imatinib mesylate dose escalation is associated with durable responses in patients with chronic myeloid leukemia post cytogenetic failure on standard-dose imatinib therapy. Blood 2009; 113: 2154–2160.

    Article  CAS  Google Scholar 

  55. Kantarjian HM, Larson RA, Guilhot F, O'Brien SG, Mone M, Rudoltz M et al. Efficacy of imatinib dose escalation in patients with chronic myeloid leukemia in chronic phase. Cancer 2009; 115: 551–560.

    Article  CAS  Google Scholar 

  56. Reardon DA, Egorin MJ, Quinn JA, Rich JN, Gururangan S, Vredenburgh JJ et al. Phase II study of imatinib mesylate plus hydroxyurea in adults with recurrent glioblastoma multiforme. J Clin Oncol 2005; 23: 9359–9368.

    Article  CAS  Google Scholar 

  57. Mahon F-X, Picard S, Marit G, Robinson P, Molimard M . Use of therapeutic drug monitoring in CML patients on imatinib. Blood 2007; 110: 1701.

    Article  CAS  Google Scholar 

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Acknowledgements

We thank Darwin Grey Communications for medical editorial assistance and Novartis Pharmaceuticals for financial support for the editorial assistance.

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Authors and Affiliations

  1. Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX, USA

    J E Cortes

  2. Division of Hematology/Oncology, Department of Medicine, Department of Pharmacology and Chemical Biology, Cancer Institute, University of Pittsburgh, Pittsburgh, PA, USA

    M J Egorin

  3. CIC INSERM 802, CHU de Poitiers, Poitiers, France

    F Guilhot

  4. Department of Clinical Pharmacology and Toxicology, Université Victor Ségalen Bordeaux 2, CHU de Bordeaux, Bordeaux, France

    M Molimard

  5. Laboratoire Hématopoïèse Leucémique et Cible Thérapeutique, INSERM U876, Université Victor Ségalen Bordeaux 2, Centre Hospitalier Universitaire de Bordeaux, Bordeaux, France

    F-X Mahon

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Correspondence to J E Cortes.

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Cortes, J., Egorin, M., Guilhot, F. et al. Pharmacokinetic/pharmacodynamic correlation and blood-level testing in imatinib therapy for chronic myeloid leukemia. Leukemia 23, 1537–1544 (2009). https://doi.org/10.1038/leu.2009.88

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