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Journal of Clinical Oncology, Vol 23, No 16 (June 1), 2005: pp. 3857-3858 © 2005 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.05.308
In Reply:Clinical Pharmacology/Oncology, Novartis Pharmaceuticals, Florham Park, NJ
We read with interest the letter by Bornhäuser et al responding to our previously published study.1 The letter raised very interesting and important issues. In fact, the pharmacokinetic (PK) profiles of the main metabolite of imatinib, CGP 74588, were also determined in our study, though not included in the article. The results in our study showed that in most patients CGP 74588 could be detected in plasma 30 minutes after oral administration of the parent compound. The PK parameters of CGP 74588 derived from the plasma concentration time curves at steady state are listed in Table 1. As shown in Table 1, the mean half-life time (t1/2;
We agree with Bornhäuser et al that imatinib might interfere with the metabolism of CYP 3A4-metabolized drugs, because it is a competitive inhibitor of CYP 3A4.5 However, it is not clear whether or not it would increase the exposure to toxic metabolites of cyclophosphamide (CY) and result in a higher incidence of extramedullary toxicities. The metabolism of CY is complex and is different from simvastatin, which is uniquely metabolized by CYP 3A4.6 CY is oxidized within hepatocytes to the active metabolite 4-hydroxycyclophosphamide (HCY) by CYP 2B6, CYP 3A4, CYP 2C9, and CYP 2A6; and in the liver, intracellular decomposition of HCY produces a DNA alkylator, phosphoramide mustard, and a toxic metabolite, acrolein.7 Azole antifungals such as itraconazole and fluconazole are known as potent inhibitors of CYP 3A4. In a randomized study comparing these two azole antifungals for prophylaxis of invasive mold infection, Marr et al7 reported significant differences in their toxicity. Specifically, patients randomized to itraconazole treatment developed higher serum bilirubin and creatinine values in the first 20 days after allogeneic stem-cell transplantation, particularly when a cyclophosphamide-containing conditioning regimen was used. Also itraconazole recipients had approximately 20% increased CY clearance, with a resultant increased exposure to HCY and HCY metabolites.7 Fluconazole recipients demonstrated lower exposure to toxic metabolites than itraconazole recipients. This might be due to the inhibition of CYP 2C9 by fluconazole and a decrease in the formation of HCY, resulting in fewer toxic HCY metabolites. Given the increased exposure to simvastatin (used as a test drug metabolized by CYP 3A4) by imatinib5 due to the inhibition of CYP 3A4, imatinib might also inhibit the metabolism of CY and result in more exposure to CY and fewer toxic metabolites like acrolein. Interestingly, in two studies8,9 in a nontransplant setting with patients with Philadelphia chromosome–positive acute lymphoblastic leukemia (PH+ ALL), imatinib was given concomitantly with a multiagent chemotherapy regimen that included intermediate or high-dose CY, with no increase in the reported toxicity of these regimens given alone. The limited data available to date in the context of stem-cell transplantation (mostly small or retrospective studies) do not suggest an increased rate of specific CY-related extramedullary toxicity.10-13 However, the interpretation of these studies is made difficult because of the underlying disease and the fact that these patients are receiving a number of other concomitant drugs, some of which potentially also interfere with the CYP 3A4 system. However, collectively, these data suggest that if there were any PK interaction between imatinib and CY, its clinical relevance may be limited. It was suggested by Bornhäuser et al "to stop imatinib at least 1 week before the start of the preparative regimen for allogeneic hematopoietic stem-cell transplantation if the underlying disease does allow to do so, in order to avoid possible interaction." This is an important practical consideration. However, at the moment, no conclusive data are available in the literature on when to stop imatinib treatment before stem-cell transplantation. In their study of Ph+ ALL patients, Wassmann et al10 reported that imatinib can be safely stopped at a median of 3 days before starting the conditioning regimen with patients transplanted for Ph+ ALL. In other reports of either ALL or chronic myelogenous leukemia patients, imatinib was stopped 10 days11 or 1 day before14 beginning the conditioning regimen. However, the decision to stop imatinib has to take into account not only the potential risk for drug interactions but also the potential risk of disease progression particularly for patients with acute leukemia. Outcomes after stem-cell transplantation are promising only if performed during complete response, therefore transplantation has to be performed rapidly following the cessation of treatment with imatinib.10 However, further study is needed to define when imatinib therapy may have to be interrupted before starting the stem-cell transplantation conditioning regimen. 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. Employment: Bin Peng, Novartis Pharmaceuticals; Renaud Capdeville, Novartis Pharmaceuticals. Stock Ownership: Renaud Capdeville, Novartis Pharmaceuticals. 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: Clinical investigation of the pharmacokinetics and pharmacodynamics of imatinib in a phase 1 trial in chronic myeloid leukemia patients. J Clin Oncol 22:935-942, 2004 2. Nikolova Z, Peng B, Hubert M, et al: Bioequivalence, safety, and tolerability of imatinib tablets compared with capsules. Cancer Chemother Pharmacol 53:433-438, 2004[CrossRef][Medline] 3. Bolton AE, Peng B, Hubert M, et al: Effect of rifampicin on the pharmacokinetics of imatinib mesylate (Glivec, STI571) in healthy subjects. Cancer Chemother Pharmacol 53:102-106, 2004[CrossRef][Medline] 4. Dutreix C, Peng B, Mehring G, et al: Pharmacokinetic interaction between ketoconazole and imatinib mesylate (Glivec) in healthy subjects. Cancer Chemother Pharmacol 54:290-294, 2004[Medline] 5. 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]
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7. Marr KA, Leisenring W, Crippa F, et al: Cyclophosphamide metabolism is affected by azole antifungals. Blood 103:1557-1559, 2004
8. Thomas DA, Faderl S, Cortes J, et al: Treatment of Philadelphia chromosome-positive acute lymphocytic leukemia with hyper-CVAD and imatinib mesylate. Blood 103:4396-4407, 2004
9. Towatari M, Yanada M, Usui N, et al: Combination of intensive chemotherapy and imatinib can rapidly induce high-quality complete remission for a majority of patients with newly diagnosed BCR-ABL positive acute lymphoblastic leukemia. Blood 104:3507-3512, 2004 10. Wassmann B, Pfeifer H, Scheuring U, et al: Therapy with imatinib mesylate (Glivec) preceding allogeneic stem cell transplantation (SCT) in relapsed or refractory Philadelphia-positive acute lymphoblastic leukemia (Ph+ALL). Leukemia 16:2358-2365, 2002[CrossRef][Medline] 11. Deininger MWN, Schleuning M, Olavarria E, et al: Safety and efficacy of glivec prior to allografting for CML and Ph-positive ALL: European experience. Bone Marrow Transplant 29:31, 2002 (suppl 2; abstr 185) 12. Shimoni A, Kroger N, Rowe JM, et al: Imatinib mesylate (STI571) in preparation for allogeneic hematopoietic stem cell transplantation and donor lymphocyte infusions in patients with Philadelphia positive acute leukemia. Leukemia 17:290-297, 2003[CrossRef][Medline] 13. Wabersich M, Krahl R, Lange T, et al: Imatinib in the pre- and post- transplantation setting in Philadelphia chromosome positive CML: A retrospective analysis. Bone Marrow Transplant 33:S149-S150, 2004 (suppl 1; abstr 615) 14. Koch M, Lang P, Bader P, et al: Successful unrelated allogeneic stem cell transplantation after treatment of lymphoid blast crisis CML with imatinib and imatinib-containing conditioning regimen in a 16-year old male. Bone Marrow Transplant 32:541-542, 2003[CrossRef][Medline]
Related Correspondence
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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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40 hours) of CGP 74588 was longer than for the parent drug imatinib (
