Cancer Chemotherapy and Pharmacology

, Volume 54, Issue 4, pp 290–294 | Cite as

Pharmacokinetic interaction between ketoconazole and imatinib mesylate (Glivec) in healthy subjects

  • Catherine Dutreix
  • Bin Peng
  • Guenther Mehring
  • Michael Hayes
  • Renaud Capdeville
  • Rolf Pokorny
  • Michael Seiberling
Original Article

Abstract

The study under discussion was a drug–drug interaction study in which the effect of ketoconazole, a potent CYP450 3A4 inhibitor, on the pharmacokinetics of Glivec (imatinib) was investigated. A total of 14 healthy subjects (13 male, 1 female) were enrolled in this study. Each subject received a single oral dose of imatinib 200 mg alone, and a single oral dose of imatinib 200 mg coadministered with a single oral dose of ketoconazole 400 mg according to a two-period crossover design. The treatment sequence was randomly allocated. Subtherapeutic imatinib doses and a short exposure were tested in order not to overexpose the healthy volunteers. There was a minimum 7-day washout period between the two sequences. Blood samples for determination of plasma concentrations were taken up to 96 h after dosing. Imatinib and CGP74588 (main metabolite of imatinib) concentrations were measured using LC/MS/MS method and pharmacokinetic parameters were estimated by a non-compartmental analysis. Following ketoconazole coadministration, the mean imatinib Cmax, AUC(0–24) and AUC(0–∞) increased significantly by 26% (P<0.005), 40% (P<0.0005) and 40% (P <0.0005), respectively. There was a statistically significant decrease in apparent clearance (CL/f) of imatinib with a mean reduction of 28.6% (P<0.0005). The mean Cmax and AUC(0–24) of the metabolite CGP74588 decreased significantly by 22.6% (P<0.005) and 13% (P<0.05) after ketoconazole treatment, although the AUC(0–∞) of CGP74588 only decreased by 5% (P=0.28). Coadministration of ketoconazole and imatinib caused a 40% increase in exposure to imatinib in healthy volunteers. Given its previously demonstrated safety profile, this increased exposure to imatinib is likely to be clinically significant only at high doses. This interaction should be considered when administering inhibitors of the CYP3A family in combination with imatinib.

Keywords

Imatinib Ketoconazole Pharmacokinetics Healthy volunteers Drug interaction 

References

  1. 1.
    Albengres E, Le Louet H, Tillement JP (1998) Systemic antifungal agents. Drug interactions of clinical significance. Drug Saf 18:83–97PubMedGoogle Scholar
  2. 2.
    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 Analyt Technol Biomed Life Sci 768:325–340CrossRefPubMedGoogle Scholar
  3. 3.
    Bennett JE (2001) Antimicrobial agents: antifungal agents. In: Hardman JG, Limbird LE (eds) Goodman and Gilman’s the pharmacological basis of therapeutics, 10th edn. McGraw-Hill Professional, NY, pp 1295–1312Google Scholar
  4. 4.
    Bolton AE, Peng B, Hubert M, et al (2004) Effect of rifampicin on the pharmacokinetics of imatinib mesylate (Gleevec, STI571) in healthy subjects. Cancer Chemother Pharmacol 53:102–106PubMedGoogle Scholar
  5. 5.
    Brown MW, Maldonado AL, Meredith CG, Speeg KV Jr (1985) Effect of ketoconazole on hepatic oxidative drug metabolism. Clin Pharmacol Ther 37:290–297PubMedGoogle Scholar
  6. 6.
    Buchdunger E, Zimmermann J, Mett H, et al (1996) Inhibition of the Abl protein-tyrosine kinase in vitro and in vivo by a 2-phenylaminopyrimidine derivative. Cancer Res 56:100–104PubMedGoogle Scholar
  7. 7.
    Buchdunger E, Cioffi CL, Law N, et al (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 295:139–145PubMedGoogle Scholar
  8. 8.
    Cortes J, Giles F, O’Brien S, et al (2003) Result of high-dose imatinib mesylate in patients with Philadelphia chromosome-positive chronic myeloid leukemia after failure of interferon-alpha. Blood 102:83–86CrossRefPubMedGoogle Scholar
  9. 9.
    Demetri GD, von Mehren M, Blanke CD, et al (2002) Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. N Engl J Med 347:472–480Google Scholar
  10. 10.
    Doble N, Shaw R, Rowland-Hill C, Lush M, Warnock DW, Keal EE (1988) Pharmacokinetic study of the interaction between rifampicin and ketoconazole. J Antimicrob Chemother 21:633–635PubMedGoogle Scholar
  11. 11.
    Druker BJ, Talpaz M, Resta D, et al (2001) Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med 344:1031–1037PubMedGoogle Scholar
  12. 12.
    Gleevec [prescribing information] (2004) Novartis Pharmaceuticals Corporation, East HanoverGoogle Scholar
  13. 13.
    Greenblatt DJ, von Moltke LL (1997) Can in vitro models predict drug interactions in vivo? A review of methods, problems, and success. In: Hori W (ed) Drug–drug interactions: analyzing in vitro–in vivo correlation. International Business Communications, Southboro, pp 2.2.1–2.2.28Google Scholar
  14. 14.
    Heinrich MC, Griffith DJ, Druker BJ, Wait CL, Ott KA, Zigler AJ (2000) Inhibition of c-kit receptor tyrosine kinase activity by STI571, a selective tyrosine kinase inhibitor. Blood 96:925–932PubMedGoogle Scholar
  15. 15.
    Hughes TP, Kaeda J, Branford S, et al (2003) Frequency of major molecular responses to imatinib or interferon alfa plus cytarabine in newly diagnosed chronic myeloid leukemia. N Engl J Med 349:1423–1432PubMedGoogle Scholar
  16. 16.
    Kantarjian H, Talpaz M, O’Brien S, et al (2004) High-dose imatinib mesylate therapy in newly diagnosed Philadelphia chromosome-positive chronic phase chronic myeloid leukaemia. Blood 103:2873–2878CrossRefPubMedGoogle Scholar
  17. 17.
    Kantarjian HM, Talpaz M, O’Brien S, et al (2003) Dose escalation of imatinib mesylate can overcome resistance to standard-dose therapy in patients with chronic myelogenous leukaemia. Blood 101:473–475CrossRefPubMedGoogle Scholar
  18. 19.
    O’Brien SG, Guilhot F, Larson RA, et al; for the IRIS Investigators (2003) Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase myeloid leukemia. N Engl J Med 348:994–1004CrossRefPubMedGoogle Scholar
  19. 20.
    O’Brien SG, Meinhardt P, Bond E, et al (2003) 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 89:1855–1859CrossRefPubMedGoogle Scholar
  20. 21.
    Okuda K, Weisberg E, Gilliland DG, Griffin JD (2001) ARG tyrosine kinase activity is inhibited by STI571. Blood 97:2440–2448PubMedGoogle Scholar
  21. 22.
    Peng B, Dutreix C, Mehring G, et al (2004) Absolute bioavailability of imatinib orally (Glivec) versus intravenous infusion. J Clin Pharmacol 44:158–162CrossRefPubMedGoogle Scholar
  22. 23.
    Peng B, Hayes M, Resta D, et al (2004) Pharmacokinetics and pharmacodynamics of imatinib in a phase I trial with chronic myeloid leukemia patients. J Clin Oncol 22:935–942CrossRefPubMedGoogle Scholar
  23. 24.
    Rubin BP, Singer S, Tsao C (2001) KIT activation is a ubiquitous feature of gastrointestinal stromal tumors. Cancer Res 61:8118–8121PubMedGoogle Scholar
  24. 25.
    Sausville EA, Elsayed Y, Monga M, Kim G (2003) Signal transduction—directed cancer treatments. Annu Rev Pharmacol Toxicol 43:199–231CrossRefPubMedGoogle Scholar
  25. 26.
    Sawyers CL, Hochhaus A, Feldman E, et al (2002) Imatinib induces hematologic and cytogenetic responses in patients with chronic myelogenous leukemia in myeloid blast crisis: results of a phase II study. Blood 99:3530–3539CrossRefPubMedGoogle Scholar
  26. 27.
    Talpaz M, Silver RT, Druker BJ (2002) Imatinib induces durable hematologic and cytogenetic responses in patients with accelerated phase chronic myeloid leukemia: results of a phase 2 study. Blood 99:1928–1937CrossRefPubMedGoogle Scholar
  27. 28.
    US Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), Center for Biologics Evaluation and Research (CBER) (1999) Guidance for industry. In vivo drug metabolism/drug interaction studies—study design, data analysis, and recommendations for dosing and labeling. Available at: http://www.fda.gov/cder/guidance/2635fnl.htm, accessed 9 March 2004
  28. 29.
    Venkatakrishnan K, von Moltke LL, Greenblatt DJ (2000) Effects of the antifungal agents on oxidative drug metabolism. Clin Pharmacokinet 38:111–180Google Scholar
  29. 30.
    von Moltke LL, Greenblatt DJ, Schmider J, Wright CE, Harmatz JS, Shader RI (1998) In vitro approaches to predicting drug interactions in vivo. Biochem Pharmacol 55:113–122PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2004

Authors and Affiliations

  • Catherine Dutreix
    • 1
  • Bin Peng
    • 2
  • Guenther Mehring
    • 1
  • Michael Hayes
    • 2
  • Renaud Capdeville
    • 1
  • Rolf Pokorny
    • 3
  • Michael Seiberling
    • 3
  1. 1.Novartis Pharma AGBaselSwitzerland
  2. 2.Novartis Pharmaceuticals CorporationEast HanoverUSA
  3. 3.Swiss Pharma Contract LtdAllschwilSwitzerland

Personalised recommendations