Abstract
Imatinib pharmacokinetics (PK) may be affected by a number of factors that are related to the disease being treated and to the response of that disease to imatinib. Patients in the phase I and phase II trials conducted by the EORTC in patients with gastrointestinal stromal tumours (GISTs) and other sarcomas had detailed blood sampling for imatinib PK on day 1 and on day 29. Patients with GISTs also had repeat sampling, using a limited sampling strategy, after approximately 12 months on therapy. This population PK study was carried out to examine what covariates affected imatinib PK in GIST patients and what PK changes occurred over time. In the model producing the best fit, low clearance (CL) correlated with low body weight and high granulocyte count, whereas low haemoglobin correlated with low volume of distribution. For a patient with 77% of the median body weight or with 1.87 times the median granulocyte count, the apparent CL is 6.53 l/h, about 70% of the typical apparent CL of 9.33 l/h; for a patient of 84% of the typical haemoglobin level, the volume of distribution is about 70%. Total white blood cell count correlated closely with granulocyte count and there was a moderate correlation between haemoglobin and albumin (r=0.454). There was a trend towards increased imatinib clearance after chronic exposure over 12 months. The typical apparent CL increased 33% from day 1. Nevertheless, the approximate 95% confidence interval of the increase of the typical apparent CL was 33±34.6%, which contains zero. It is not yet clear whether this is a significant factor in the amelioration of imatinib toxicity that occurs with time or is related to disease control, and further work is required to confirm this observation.
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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 Anal Technol Biomed Life Sci 768:325–340
Beal SL, Sheiner LB (eds) (1998) NONMEM users’ guide. NONMEM Project Group, University of California, San Francisco
Benjamin RS, Rankin C, Fletcher C, Blanke C, Von Mehren M, Maki R, Bramwell V, Baker L, Borden E, Demetri GD (2003) Phase III dose-randomized study of imatinib mesylate (STI571) for GIST: intergroup S0033 early results (abstract 3271). Proc Am Soc Clin Oncol 22:814
Buchdunger E, Cioffi CL, Law N, Stover D, Ohno JS, 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
Demetri GD, von Mehren M, Blanke CD, Van den Abbeele AD, Eisenberg B, Roberts PJ, Heinrich MC, Tuveson DA, Singer S, Janicek M, Fletcher JA, Silverman SG, Silberman SL, Capdeville R, Kiese B, Peng B, Dimitrijevic S, Druker BJ, Corless C, Fletcher CD, Joensuu H (2003) Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. N Engl J Med 347:472–480
Druker BJ, Talpaz M, Resta DJ, Peng B, Buchdunger E, Ford MF, Lydon NB, Kantarjian H, Capdeville R, Ohno-Jones S, Sawyers CL (2001) Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med 344:1031–1037
Druker BJ, Sawyers CL, Kantarjian H, Resta DJ, Reese SF, Ford MJ 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
Gambacorti-Passerini C, Zucchetti M, Russo D, Frapolli R, Verga M, Bungaro S, Tornaghi L, Rossi F, Pioltelli P, Polgiani E, Alberti D, Corneo G, D’Incalci M (2003) α1 Acid glycoprotein binds to imatinib (STI571) and substantially alters its pharmacokinetics in chronic myeloid leukemia patients. Clin Cancer Res 9:625–632
Heinrich MC, Corless CL, Duensing A, McGreevey L, Chen CJ, Joseph N, Singer S, Griffith DJ, Haley A, Town A, Demetri GD, Fletcher CD, Fletcher JA (2003) PDGFRA activating mutations in gastrointestinal stromal tumors. Science 299:708–710
Heinrich MC, Corless CL, Demetri GD, Blanke CD, von Mehren M, Joensuu H, McGreevey LS, Chen CJ, Van den Abbeele AD, Druker BJ, Kiese B, Eisenberg B, Roberts PJ, Singer S, Fletcher CD, Silberman S, Dimitrijevic S, Fletcher JA (2003) Kinase mutations and imatinib response in patients with metastatic gastrointestinal stromal tumor. J Clin Oncol 21:4342–4349
Hirota S, Isozaki K, Moriyama Y, Hashimoto K, Nishida T, Ishiguro S, Kawano K, Nanada M, Kurata A, Takeda M, Tunio GM, Matsuzawa Y, Kankura Y, Shinomura Y, Kitamura Y (1998) Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors. Science 279:577–580
Joensuu H, Roberts PJ, Sarlomo-Rikala M, Andersson LC, Tervahartiala P, Tuveson D, Silberman SL, Capdeville R, Dimitrijevic S, Druker B, Demetri GD (2001) Effect of the tyrosine kinase inhibitor STI571 in a patient with a metastatic gastrointestinal stromal tumor. N Engl J Med 344:1052–1056
Judson IR, Donato Di Paola E, Verweij J, Van Glabbeke M, Ma P, Peng B, Dimitrijevic S, Van Oosterom A (2003) Population pharmacokinetic (PK) analysis and PK-pharmacodynamic (PD) correlations in phase I/II trial of imatinib in gastrointestinal stromal tumours (GIST) conducted by the European Organisation for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group (abstract 3287). Proc Am Soc Clin Oncol 22:818
Kindblom L-G, Remotti HE, Aldenborg F, Meis-Kindblom JM (1998) Gastrointestinal pacemaker cell tumor (GIPACT): gastrointestinal stromal tumors show phenotypic characteristics of the interstitial cells of Cajal. Am J Pathol 152:1259–1269
Peng B, Schmidli H, Riviere GJ, Racine A, Capdeville R (2002) Population pharmacokinetics of imatinib in patients with newly diagnosed Philadelphia chromosome positive (Ph+) chronic myelogenous leukemia in chronic phase. Blood 100:784a
Peng B, Dutreix C, Mehring G, Hayes M, Ben-Am M, Sieberling M, Pokorny R, Capdeville R, Lloyd P (2004) Absolute bioavailability of imatinib (Glivec®) orally versus intravenous infusion. J Clin Pharmacol 44:158–162
Van Oosterom AT, Judson I, Verweij J, Stroobants S, Donato Di Paola E, Dimitrijevic S, Martens M, Webb A, Sciot R, van Glabbeke M, Silberman S, Nielsen OS (2001) For the European Organisation for Research into Treatment for Cancer (EORTC. Safety and efficacy of imatinib (STI571) in metastatic gastrointestinal stromal tumours: a phase I study. Lancet 358:1421–1423
Verweij J, van Oosterom A, Blay J-Y, Judson I, Rodenhuis S, van der Graaf W, Radford J, Le Cesne A, Hogendoorn PC, Donato di Paola E, Brown M, Nielsen OS (2003) Imatinib mesylate (STI-571 Glivec, Gleevec) is an active agent for gastrointestinal stromal tumours, but does not yield responses in other soft-tissue sarcomas that are unselected for a molecular target. Results from an EORTC Soft Tissue and Bone Sarcoma Group phase II study. Eur J Cancer 39:1976–1977
Verweij J, Casali P, Zalcberg J, le Cesne A, Reichardt P, Blay J-Y, Issels R, van Oosterom A, Hogendoorn P, van Glabbeke M, Judson I (2004) Progression-free survival in gastro-intestinal stromal tumours with high-dose imatinib: randomised trial. Lancet 364:1127–1134
Zalcberg J, Verweij J, Casali PG, Le Cesne A, Reichardt P, Blay J-Y, Issels RD, Glabbeke M, Evrard V, Judson IR (2004) Outcome of patients with advanced gastro-intestinal stromal tumors (GIST) crossing over to a daily imatinib dose of 800 mg (HD) after progression on 400 mg (LD)—an international, intergroup study of the EORTC, ISG and AGITG (abstract 9004). Proc Am Soc Clin Oncol 23
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Judson, I., Ma, P., Peng, B. et al. 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, 379–386 (2005). https://doi.org/10.1007/s00280-004-0876-0
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DOI: https://doi.org/10.1007/s00280-004-0876-0