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Journal of Clinical Oncology, Vol 26, No 4 (February 1), 2008: pp. 521-522 © 2008 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.14.5110
Imatinib for Patients With Liver or Kidney Dysfunction: No Need to Modify the DoseSarcoma Unit, Royal Marsden Hospital, London, United Kingdom Imatinib, an orally administered inhibitor of the tyrosine kinases Ableson leukemia virus (ABL), KIT, and platelet-derived growth factor receptor (PDGFR), is of course well known as the first small molecule inhibitor of tyrosine kinases to be licensed for cancer treatment. Imatinib has become standard therapy for chronic myeloid leukemia, driven by the BCR-ABL fusion gene, and for metastatic gastrointestinal stromal tumor, a disease usually driven by mutation-activated KIT, or PDGFRA.1-5 The pharmacokinetics (PK) of imatinib and its route of elimination are well known. It is well absorbed orally, with approximately 100% bioavailability, and metabolized in the liver, mainly via CYP3A4/5.6,7 The main metabolite, CGP74588, is known to be active, and the elimination of this and other metabolites is more than 90% through the bile. The elimination half-life is approximately 18 hours, with two- to three-fold accumulation at steady-state.7 There is no evidence for induction of metabolism, but one study reported an increase in clearance over time in patients with gastrointestinal stromal tumor.8 There are a number of important potential drug interactions, with rifampicin9 and antiepileptic drugs such as phenytoin, which can increase imatinib clearance and reduce imatinib plasma concentration, and warfarin, for which the reverse applies (ie, imatinib can potentiate the anticoagulant effect). Grapefruit juice may also increase imatinib levels. It is routine for a new medicinal product to be investigated in patients with impaired organ function to look for changes in pharmacokinetics (PK) and determine whether dose modifications are required for reasons of safety or efficacy. There are well-known examples of anticancer drugs for which the dose needs to be reduced for patients with impaired liver function, such as epirubicin10 and docetaxel,11 or impaired renal function, such as etoposide.12 Conversely, in the case of carboplatin, a drug that is almost exclusively cleared by the kidneys, it is important to tailor the dose according to glomerular filtration rate, as much to ensure the delivery of an adequate dose as to prevent overdosing.13 PK behavior is usually determined early in the development of a new agent. In the case of imatinib, PK data were obtained in patients with chronic myeloid leukemia and used to examine not only the oral bioavailability, impact of food on absorption,6 interpatient variability in drug exposure, and clearance, but also a threshold level of drug exposure, and by implication dose, to ensure efficacy.7 Although the vast majority of patients with gastrointestinal tumor respond to imatinib, certainly those with the favorable exon 11 mutations in KIT,4,14 data are lacking to correlate response with PK or to explain the apparent value of increasing the dose in patients with acquired resistance to standard dose15 or those with the less favorable exon 9 mutation in KIT.16 Two articles in this issue of Journal of Clinical Oncology examine the potential impact of impaired organ function on the PK and potential toxicity of imatinib. Both studies were conducted as phase I trials over the imatinib dose range 100 to 800 mg/d, with progressively more cautious starting doses for moderate or severe dysfunction. Gibbons et al17 studied patients with renal dysfunction, ranging from creatinine clearance (CrCL) more than 60 mL/min to less than 20 mL/min. Ramanathan et al18 studied patients with liver dysfunction as defined by the National Cancer Institute Organ Dysfunction Working Group scheme using only two parameters: total bilirubin and AST, where severe dysfunction is defined by total bilirubin more than 3 to 10x the upper limit of normal. The results of these two studies are reassuring for those of us prescribing imatinib, but they are nevertheless surprising in several ways. It may also be a surprise that PK information on imatinib in patients with impaired organ function has only now become available. In part this is undoubtedly due to the astonishing speed with which the drug entered routine clinical use, but it also emphasizes the difficulty of conducting such studies, especially in patients with impaired liver function. In addition, Pharma is not required to do this before the granting of a product license. In the study of patients with liver dysfunction,18 somewhat surprisingly, no relationship was observed between imatinib PK and the severity of dysfunction. All dose-limiting toxicities occurred in the mild liver dysfunction group, most probably because the duration of treatment was progressively shorter with worsening function, reflecting the poor prognosis of patients with metastatic liver disease who have elevated total bilirubin. The authors concluded that patients with moderate or severe liver dysfunction could either be dosed at 400 mg/d, with careful monitoring of liver function and toxicity, or commenced on 300 mg/d, with a view to rapidly escalating to 400 mg in the absence of severe toxicity.
So what about renal function? This was a somewhat different story. Gibbons et al17 showed that it was possible to complete the dose escalation from 100 to 800 mg/d even in patients with severe renal dysfunction, with no definition of maximum-tolerated dose in any group and no increase in toxicity with progressively worsening renal function. However, there was a progressive decrease in clearance and concomitant increase in maximum concentration and area under the curve with worsening function. It has been reported that patients with chronic renal failure have reduced hepatic cytochrome P450 activity,19-21 but the metabolite (CGP75588) to imatinib ratio was unaltered, except in the two patients in the severe renal dysfunction group, perhaps suggesting that metabolism was not affected by renal dysfunction. There was a progressive increase in The article concludes with the recommendation that no dose modifications are required for patients with mild (CrCL of 40 to 59 mL/min) or moderate renal dysfunction (CrCL of 20 to 39 mL/min), but in patients with severe dysfunction, there is still a need for caution owing to a lack of data. In conclusion, imatinib PK are, rather surprisingly, unaffected by impaired liver function but are influenced by impaired renal function, resulting in reduced clearance and increased drug exposure, but without any major increase in toxicity. There is therefore some need for caution when treating patients with chronic renal failure. However, liver dysfunction does not seem to affect the clearance of the drug, which can safely be administered at the recommended dose in this setting, provided liver function is carefully monitored. AUTHOR'S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. For a detailed description of the disclosure 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 in Information for Contributors. Employment or Leadership Position: None Consultant or Advisory Role: Ian R. Judson, Novartis (C), Pfizer (C) Stock Ownership: None Honoraria: Ian R. Judson, Novartis, Pfizer Research Funding: None Expert Testimony: None Other Remuneration: None REFERENCES 1. Druker BJ, Tamura S, Buchdunger E, et al: Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr-Abl positive cells. Nat Med 2:561-566, 1996[CrossRef][Medline] 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. Joensuu H, Roberts PJ, Sarlomo-Rikala M, et al: Effect of the tyrosine kinase inhibitor STI571 in a patient with a metastatic gastrointestinal stromal tumor. N Engl J Med 344:1052-1056, 2001 4. Verweij J, Casali PG, Zalcberg J, et al: Progression-free survival in gastrointestinal stromal tumours with high-dose imatinib: Randomised trial. Lancet 364:1127-1134, 2004[CrossRef][Medline] 5. Heinrich MC, Corless CL, Demetri GD, et al: Kinase mutations and imatinib response in patients with metastatic gastrointestinal stromal tumor. J Clin Oncol 21:4342-4349, 2003 6. Peng B, Dutreix C, Mehring G, et al: Absolute bioavailability of imatinib (Glivec) orally versus intravenous infusion. J Clin Pharmacol 44:158-162, 2004 7. 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 8. 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[CrossRef][Medline] 9. Bolton AE, Peng B, Hubert M, et al: Effect of rifampicin on the pharmacokinetics of imatinib mesylate (Gleevec, STI571) in healthy subjects. Cancer Chemother Pharmacol 53:102-106, 2004[CrossRef][Medline] 10. Twelves CJ, Dobbs NA, Michael Y, et al: Clinical pharmacokinetics of epirubicin: The importance of liver biochemistry tests. Br J Cancer 66:765-769, 1992[Medline] 11. Bruno R, Hille D, Riva A, et al: Population pharmacokinetics/pharmacodynamics of docetaxel in phase II studies in patients with cancer. J Clin Oncol 16:187-196, 1998 12. Joel SP, Shah R, Clark PI, et al: Predicting etoposide toxicity: Relationship to organ function and protein binding. J Clin Oncol 14:257-267, 1996[Abstract] 13. Calvert AH, Newell DR, Gumbrell LA, et al: Carboplatin dosage: Prospective evaluation of a simple formula based on renal function. J Clin Oncol 7:1748-1756, 1989[Abstract] 14. Verweij J, van Oosterom A, Blay JY, et al: 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 39:2006-2011, 2003[CrossRef][Medline] 15. Zalcberg JR, Verweij J, Casali PG, et al: Outcome of patients with advanced gastro-intestinal stromal tumours crossing over to a daily imatinib dose of 800 mg after progression on 400 mg. Eur J Cancer 41:1751-1757, 2005[CrossRef][Medline] 16. Debiec-Rychter M, Sciot R, Le Cesne A, et al: KIT mutations and dose selection for imatinib in patients with advanced gastrointestinal stromal tumours. Eur J Cancer 42:1093-1103, 2006[CrossRef][Medline] 17. Gibbons J, Egorin ML, Ramanathan RK, et al: 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, 2008 18. Ramanathan RK, Egorin MJ, Takimoto CHM, et al: Phase I and pharmacokinetic study of imatinib mesylate in patients with advanced malignancies and varying degrees of liver dysfunction: A study by the National Cancer Institute Organ Dysfunction Working Group. J Clin Oncol 26:563-569, 2008 19. Leblond F, Guevin C, Demers C, et al: Downregulation of hepatic cytochrome P450 in chronic renal failure. J Am Soc Nephrol 12:326-332, 2001 20. Touchette MA, Slaughter RL: The effect of renal failure on hepatic drug clearance. Dicp 25:1214-1224, 1991[Abstract] 21. Dowling TC, Briglia AE, Fink JC, et al: Characterization of hepatic cytochrome p4503A activity in patients with end-stage renal disease. Clin Pharmacol Ther 73:427-434, 2003[CrossRef][Medline] 22. Gambacorti-Passerini C, Zucchetti M, Russo D, et al: Alpha1 acid glycoprotein binds to imatinib (STI571) and substantially alters its pharmacokinetics in chronic myeloid leukemia patients. Clin Cancer Res 9:625-632, 2003
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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1-acid glycoprotein (AGP) with worsening function. Imatinib is known to bind strongly to AGP, which might then have the effect of reducing imatinib clearance by reducing the free fraction.
