Abstract
Purpose
The European Society for Medical Oncology recommends therapeutic drug monitoring (TDM) for imatinib, based on total plasma concentrations in cases of sub-optimal response, failure, or adverse events. Imatinib is highly bound to alpha-1 acid glycoprotein (AGP) in the plasma. We determined the unbound plasma fraction of both imatinib and its main active metabolite (N-desmethyl-imatinib) in plasma from 44 patients. The objective was to quantify the inter-individual variability of the protein binding of imatinib in order to discuss the potential benefits and limits of TDM of free plasma concentrations.
Patients and methods
The quantification of unbound fraction of imatinib and N-desmethyl-imatinib was performed using plasma ultrafiltration coupled with LC–MS/MS measurement. 60 pre-dose plasma samples were obtained at steady state within TDM in 44 chronic myeloid leukemia patients.
Results
The mean unbound fractions of imatinib and N-desmethyl-imatinib were 2.94 and 5.10 %, respectively, with inter-individual variability (CV in %) of 57 % for imatinib and 71 % for the metabolite. For 11 patients, repeated blood sampling gave a mean intra-individual variability of 28 % for imatinib and 34 % for N-desmethyl-imatinib. No correlation was observed between these measured individual imatinib unbound fraction values and those obtained using an equation based on AGP levels previously proposed by Widmer et al. The mean N-desmethyl-imatinib/imatinib ratio was determined for both total (0.69) and unbound (1.10) concentrations, with inter-individual variabilities of 71 and 86 %, respectively.
Conclusion
The large inter-individual variability for the unbound fraction of both imatinib and N-desmethyl-imatinib warrants further evaluation of the pharmacokinetic–pharmacodynamic relationship as a potential relevant marker of imatinib therapeutic outcomes.
References
Arellano C, Gandia P, Lafont T, Jongejan R, Chatelut E (2012) Determination of bound fraction of imatinib and N-desmethyl imatinib—validation of an UPLC-MS/MS assay and ultrafiltration method. J Chromatogr B Anal Technol Biomed Life Sci 907:94–100
Baccarani M, Dreyling M (2009) Chronic myelogenous leukemia: ESMO clinical recommendations for diagnosis, treatment and follow-up. Ann Oncol 20(Suppl 4):105–107
Buchdunger E, Cioffi CL, Law N, Stover D, Ohno-Jones S, Druker BJ, Lydon NB (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 295:139–145
Delbaldo C, Chatelut E, Re M, Deroussent A, Seronie-Vivien S, Jambu A, Berthaud P, Le Cesne A, Blay JY, Vassal G (2006) Pharmacokinetic-pharmacodynamic relationships of imatinib and its main metabolite in patients with advanced gastrointestinal stromal tumors. Clin Cancer Res 12:6073–6078
Demetri GD, Wang Y, Wehrle E, Racine A, Nikolova Z, Blanke CD, Joensuu H, von Mehren M (2009) Imatinib plasma levels are correlated with clinical benefit in patients with unresectable/metastatic gastrointestinal stromal tumors. J Clin Oncol 27:3141–3147
Druker BJ, Sawyers CL, Kantarjian H, Resta DJ, Reese SF, Ford JM, Capdeville R, Talpaz M (2001) Activity of a specific inhibitor of the BCR-ABL tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia chromosome. N Engl J Med 344:1038–1042
Eechoute K, Fransson MN, Reyners AK, de Jong FA, Sparreboom A, van der Graaf WT, Friberg LE, Schiavon G, Wiemer EA, Verweij J, Loos WJ, Mathijssen RH, De Giorgi U (2012) A long-term prospective population pharmacokinetic study on imatinib plasma concentrations in GIST patients. Clin Cancer Res 18:5780–5787
Fitos I, Visy J, Zsila F, Mady G, Simonyi M (2006) Selective binding of imatinib to the genetic variants of human alpha1-acid glycoprotein. Biochim Biophys Acta 1760:1704–1712
Gambacorti-Passerini C, Barni R, le Coutre P, Zucchetti M, Cabrita G, Cleris L, Rossi F, Gianazza E, Brueggen J, Cozens R, Pioltelli P, Pogliani E, Corneo G, Formelli F, D’Incalci M (2000) Role of alpha1 acid glycoprotein in the in vivo resistance of human BCR-ABL(+) leukemic cells to the abl inhibitor STI571. J Natl Cancer Inst 92:1641–1650
Gambacorti-Passerini C, Zucchetti M, Russo D, Frapolli R, Verga M, Bungaro S, Tornaghi L, Rossi F, Pioltelli P, Pogliani E, Alberti D, Corneo G, D’Incalci M (2003) Alpha1 acid glycoprotein binds to imatinib (STI571) and substantially alters its pharmacokinetics in chronic myeloid leukemia patients. Clin Cancer Res 9:625–632
Gibbons J, Egorin MJ, Ramanathan RK, Fu P, Mulkerin DL, Shibata S, Takimoto CH, Mani S, LoRusso PA, Grem JL, Pavlick A, Lenz HJ, Flick SM, Reynolds S, Lagattuta TF, Parise RA, Wang Y, Murgo AJ, Ivy SP, Remick SC (2008) Phase I and pharmacokinetic study of imatinib mesylate in patients with advanced malignancies and varying degrees of renal dysfunction: a study by the National Cancer Institute Organ Dysfunction Working Group. J Clin Oncol 26:570–576
Gschwind HP, Pfaar U, Waldmeier F, Zollinger M, Sayer C, Zbinden P, Hayes M, Pokorny R, Seiberling M, Ben-Am M, Peng B, Gross G (2005) Metabolism and disposition of imatinib mesylate in healthy volunteers. Drug Metab Dispos 33:1503–1512
Haouala A, Widmer N, Guidi M, Montemurro M, Leyvraz S, Buclin T, Eap CB, Decosterd L, Csajka C (2012) Prediction of free imatinib concentrations based on total plasma levels in gist patients. Br J Clin Pharmacol (in press)
Kretz O, Weiss HM, Schumacher MM, Gross G (2004) In vitro blood distribution and plasma protein binding of the tyrosine kinase inhibitor imatinib and its active metabolite, CGP74588, in rat, mouse, dog, monkey, healthy humans and patients with acute lymphatic leukaemia. Br J Clin Pharmacol 58:212–216
Larghero J, Leguay T, Mourah S, Madelaine-Chambrin I, Taksin AL, Raffoux E, Bastie JN, Degos L, Berthaud P, Marolleau JP, Calvo F, Chomienne C, Mahon FX, Rousselot P (2003) Relationship between elevated levels of the alpha 1 acid glycoprotein in chronic myelogenous leukemia in blast crisis and pharmacological resistance to imatinib (Gleevec) in vitro and in vivo. Biochem Pharmacol 66:1907–1913
Le Guellec C, Simon N, Hulot JS, Billaud EM, Marquet P (2009) Evidence-based therapeutic drug monitoring: a systematic assessment. La Lettre du Pharmacologue 23:29–33
Mlejnek P, Dolezel P, Faber E, Kosztyu P (2011) Interactions of N-desmethyl imatinib, an active metabolite of imatinib, with P-glycoprotein in human leukemia cells. Ann Hematol 90:837–842
Picard S, Titier K, Etienne G, Teilhet E, Ducint D, Bernard MA, Lassalle R, Marit G, Reiffers J, Begaud B, Moore N, Molimard M, Mahon FX (2007) Trough imatinib plasma levels are associated with both cytogenetic and molecular responses to standard-dose imatinib in chronic myeloid leukemia. Blood 109:3496–3499
Reardon DA, Egorin MJ, Quinn JA, Rich JN, Gururangan S, Vredenburgh JJ, Desjardins A, Sathornsumetee S, Provenzale JM, Herndon JE 2nd, Dowell JM, Badruddoja MA, McLendon RE, Lagattuta TF, Kicielinski KP, Dresemann G, Sampson JH, Friedman AH, Salvado AJ, Friedman HS (2005) Phase II study of imatinib mesylate plus hydroxyurea in adults with recurrent glioblastoma multiforme. J Clin Oncol 23:9359–9368
Shukla S, Sauna ZE, Ambudkar SV (2008) Evidence for the interaction of imatinib at the transport-substrate site(s) of the multidrug-resistance-linked ABC drug transporters ABCB1 (P-glycoprotein) and ABCG2. Leukemia 22:445–447
Smith P, Bullock JM, Booker BM, Haas CE, Berenson CS, Jusko WJ (2004) The influence of St. John’s wort on the pharmacokinetics and protein binding of imatinib mesylate. Pharmacotherapy 24:1508–1514
Streit F, Binder L, Hafke A, Brandhorst G, Braulke F, Haase D, Armbrust T, Cameron S, Ramadori G, Oellerich M, Walson P (2011) Use of total and unbound imatinib and metabolite LC-MS/MS assay to understand individual responses in CML and GIST patients. Ther Drug Monit 33:632–643
White DL, Saunders VA, Dang P, Engler J, Zannettino AC, Cambareri AC, Quinn SR, Manley PW, Hughes TP (2006) 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 108:697–704
Widmer N, Decosterd LA, Csajka C, Leyvraz S, Duchosal MA, Rosselet A, Rochat B, Eap CB, Henry H, Biollaz J, Buclin T (2006) Population pharmacokinetics of imatinib and the role of alpha-acid glycoprotein. Br J Clin Pharmacol 62:97–112
Acknowledgments
The authors are grateful to Pr. J. Woodley and Dr. M. White-Koning for help with the English language.
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Gandia, P., Arellano, C., Lafont, T. et al. Should therapeutic drug monitoring of the unbound fraction of imatinib and its main active metabolite N-desmethyl-imatinib be developed?. Cancer Chemother Pharmacol 71, 531–536 (2013). https://doi.org/10.1007/s00280-012-2035-3
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DOI: https://doi.org/10.1007/s00280-012-2035-3