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Journal of Clinical Oncology, Vol 23, No 16 (June 1), 2005: pp. 3855-3856 © 2005 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.05.246
Elimination of Imatinib Mesylate and Its Metabolite N-Desmethyl-ImatinibDepartment of Hematology/Oncology, University Hospital, Dresden, Germany To the Editor: We read with interest the manuscript by Peng et al1 on the pharmacodynamics and pharmacokinetics (PK) of imatinib mesylate (imatinib) in patients with chronic myeloid leukemia (CML) enrolled onto a dose-finding trial.2 The authors observed a dose-proportional PK profile and a 1.5-to-3–fold accumulation after repeated dosing. In addition, they found a correlation between the dose administered and the dynamics of hematologic response in chronic-phase CML patients. No information was provided on the PK profiles of metabolites like N-desmethyl-imatinib, which have also been shown to block the protein tyrosine kinase associated with bcr-abl. Allogeneic hematopoietic stem-cell transplantation is performed with increasing frequency in patients who have received imatinib for several months. Imatinib can interfere with the metabolism of cytostatic drugs like cycylophosphamide by competing for metabolization by cytochrome p450 3A4.3,4 Comparable effects have already been established for azole antifungals.5 One potential result of this interaction could be a higher incidence of extramedullary toxicities after myeloablative conditioning therapy. Because imatinib and its main metabolite may be relevant for this interaction, it would be important for clinicians to know the elimination kinetics of both compounds after long-term therapy with imatinib mesylate. We therefore performed detailed PK analyses of imatinib and its main metabolite in patients with Philadelphia chromosome–positive CML (n = 4) and acute lymphoblastic leukemia (ALL; n = 2) who were scheduled for allogeneic transplantation and therefore had to stop taking imatinib. The median dose of imatinib administered was 400 mg/d (range, 300 to 800 mg). Patients with CML were on imatinib for 12, 16, 18, and 21 months, whereas ALL patients had received imatinib for 2 and 3 months, respectively. Complete 24-hour plasma PK analyses of imatinib and N-desmethyl-imatinib were performed after the last morning dose (samples were collected at 0, 0.5, 1, 2, 2.5, 5, 6, 7, 8, 12, and 24 hours after the last drug administration). In addition, urine was collected over a period of 24 hours. Subsequently, the respective plasma levels of imatinib and N-desmethyl-imatinib were determined every 24 hours, with the goal to start conditioning therapy when imatinib and its metabolite reached levels of less than 100 ng/mL. Plasma and urine concentrations of imatinib and its metabolite were determined by a high-performance liquid chromatography assay, as previously described.6 Tables 1 and 2 list the PK results for imatinib and its metabolite calculated for a dose of 300 mg/m2 once daily, assuming 100% imatinib absorption.7 The data obtained for imatinib mesylate are in line with the results reported by Peng et al1 for steady-state conditions. We have now provided for the first time more detailed elimination kinetics of N-desmethyl-imatinib. The mean ratio of the plasma concentration of imatinib and its metabolite was 5.18 (18%). A mean half-life of 74.3 hours was calculated for N-desmethyl-imatinib. It took up to 190 hours for the lower detection limit for the metabolite to be reached. Only 5% to 10% of imatinib and N-desmethyl-imatinib underwent renal elimination. Our data suggest that the major metabolite N-desmethyl-imatinib has to be taken into account when discussing possible interactions of imatinib with other drugs administered. The prolonged elimination kinetics of this metabolite may be relevant for questions of efficacy and cumulative toxicities of combination treatments. If possible interactions of imatinib and its metabolite with cytostatic drugs and antifungals need to be avoided, we suggest stopping imatinib administration at least 1 week before the start of the preparative regimen, if the underlying disease so allows.
Authors' Disclosures of Potential Conflicts of Interest The following authors or their immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. Research Funding: Martin Bornhäuser, Novartis. Eberhard Schleyer, Novartis. For a detailed description of these categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section of Information for Contributors found in the front of every issue.
REFERENCES
1. Peng B, Hayes M, Resta D, et al: Pharmacokinetics and pharmacodynamics of imatinib in a phase I trial with chronic myeloid leukemia patients. J Clin Oncol 22:935-942, 2004
2. Druker BJ, Talpaz M, Resta DJ, et al: Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med 344:1031-1037, 2001
3. McDonald GB, Slattery JT, Bouvier ME, et al: Cyclophosphamide metabolism, liver toxicity, and mortality following hematopoietic stem cell transplantation. Blood 101:2043-2048, 2003 4. O'Brien SG, Meinhardt P, Bond E, 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 89:1855-1859, 2003[CrossRef][Medline]
5. Marr KA, Leisenring W, Crippa F, et al: Cyclophosphamide metabolism is affected by azole antifungals. Blood 103:1557-1559, 2004 6. Schleyer E, Pursche S, Kohne CH, et al: Liquid chromatographic method for detection and quantitation of STI-571 and its main metabolite N-desmethyl-STI in plasma, urine, cerebrospinal fluid, culture medium and cell preparations. J Chromatogr B Analyt Technol Biomed Life Sci 799:23-36, 2004[Medline]
7. Peng B, Dutreix C, Mehring G, et al: Absolute bioavailability of imatinib (Glivec) orally versus intravenous infusion. J Clin Pharmacol 44:158-162, 2004 Related Reply
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Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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