Clinical Drug Investigation

, Volume 31, Issue 3, pp 169–179 | Cite as

Effects of Nilotinib on Single-Dose Warfarin Pharmacokinetics and Pharmacodynamics

A Randomized, Single-Blind, Two-Period Crossover Study in Healthy Subjects
  • Ophelia Q.P. Yin
  • Neil Gallagher
  • Deirdre Fischer
  • Lily Zhao
  • Wei Zhou
  • Elisabeth Leroy
  • Georg Golor
  • Horst Schran
Original Research Article

Abstract

Background and Objective: Nilotinib (Tasigna®), a highly selective and potent BCR-ABL tyrosine kinase inhibitor, is approved for the treatment of chronic myeloid leukaemia in the chronic phase (CML-CP) and the accelerated phase (CML-AP) in patients resistant or intolerant to prior therapy, including imatinib. Nilotinib has shown competitive inhibition of cytochrome P450 enzyme (CYP) 2C9 in vitro, but its effect on CYP2C9 activity in humans is unknown. This study evaluated the effects of nilotinib on the pharmacokinetics and pharmacodynamics of warfarin, a sensitive CYP2C9 substrate, in healthy subjects.

Methods: Twenty-four subjects (six female, 18 male, aged 21–65 years) were enrolled to receive a single oral dose of warfarin 25 mg with either a single oral dose of nilotinib 800 mg or matching placebo (all administered 30 minutes after consumption of a high-fat meal) in a crossover design. Serial blood samples were collected post-dose for determining serum concentrations of nilotinib and plasma concentrations of S- and R-warfarin. Prothrombin time (PT) and international normalized ratio (INR) values were determined as pharmacodynamic measures of warfarin activity. CYP2C9 genotyping was performed in all subjects using TaqMan® assay.

Results: Sixteen subjects were identified as CYP2C9 extensive metabolizers (EMs) and eight as intermediate metabolizers (IMs). There were no CYP2C9 poor metabolizers. Pharmacokinetic parameters of S- and R-warfarin were similar between the two treatments (warfarin + nilotinib vs warfarin alone) in both the EM and the IM groups. The geometric mean ratios (90% CIs) for the maximum concentration in plasma (Cmax) and area under the concentration-time curve from time zero to infinity (AUC) of S-warfarin in plasma in all subjects were 0.98 (0.95, 1.02) and 1.03 (0.99, 1.07), respectively, and for R-warfarin 1.00 (0.96, 1.04) and 1.02 (0.99, 1.04), respectively. Mean ratios for the maximum observed value and AUC from time zero to the last sampling time for PT were 1.00(0.96,1.04) and 1.00(0.98,1.02), respectively, and for the maximum observed value for INR and the AUC from time zero to the last sampling time for INR were 1.00(0.97,1.03) and 1.00(0.99, 1.01), respectively. Mean ± SD serum nilotinib Cmax was 1872 ±560 ng/mL, which is comparable to steady-state Cmax in CML and gastrointestinal stromal tumour patients receiving twice-daily 400 mg doses. Adverse events observed following either treatment were generally consistent with the known safety profiles of both drugs, and no new safety issues were observed.

Conclusion: The study results demonstrate that nilotinib has no effect on single-dose warfarin pharmacokinetics and pharmacodynamics. This implies that nilotinib is unlikely to inhibit CYP2C9 activity in human subjects. These findings suggest that warfarin and nilotinib may be used concurrently as needed.

Notes

Acknowledgements

The authors thank the nursing and research staff members at PAREXEL International GmbH for their assistance in the conduct of the clinical study. The study was financially supported by Novartis Pharmaceuticals Corporation.

Drs Ophelia Yin, Neil Gallagher, Deirdre Fischer, Lily Zhao, Wei Zhou, Elisabeth Leroy and Horst Schran are employees of Novartis Pharmaceuticals Corporation. Georg Golor is an employee of PAREXEL International GmbH.

References

  1. 1.
    Weisberg E, Manley P, Mestan J, et al. AMN107 (nilotinib) a novel and selective inhibitor of BCR-ABL. Br J Cancer 2006; 94: 1765–9PubMedCrossRefGoogle Scholar
  2. 2.
    Verstovsek S, Golemovic M, Kantarjian H, et al. AMN107, a novel aminopyrimidine inhibitor of p190 BCR-ABL activation and of in vitro proliferation of Philadelphia-positive acute lymphoblastic leukemia cells. Cancer 2005; 104: 1230–6PubMedCrossRefGoogle Scholar
  3. 3.
    Golemovic M, Verstovsek S, Giles F, et al. AMN107, a novel aminopyrimidine inhibitor of Bcr-Abl, had in vitro activity against imatinib-resistant chronic myeloid leukemia. Clin Cancer Res 2005; 11: 4941–7PubMedCrossRefGoogle Scholar
  4. 4.
    Weisberg E, Manley PW, Breitenstein W, et al. Characterization of AMN107, a selective inhibitor of native and mutant Bcr-Abl. Cancer Cell 2005; 7: 129–41PubMedCrossRefGoogle Scholar
  5. 5.
    Nilotinib (Tasigna®) [package insert]. East Hanover (NJ): Novartis Pharmaceuticals Corporation, 2007 OctGoogle Scholar
  6. 6.
    Kantarjian H, Giles F, Wunderle L, et al. Nilotinib in imatinib-resistant CML and Philadelphia chromosome-positive ALL. N Engl J Med 2006; 354: 2542–51PubMedCrossRefGoogle Scholar
  7. 7.
    Bjornsson TD, Callaghan JT, Einolf HJ, et al. The conduct of in vitro and in vivo drug-drug interaction studies: a PhRMA perspective. J Clin Pharmacol 2003; 43: 443–69PubMedGoogle Scholar
  8. 8.
    U.S. Food and Drug Administration (FDA). Guidance for industry: drug interaction studies — study design, data analysis, and implications for dosing and labeling. Rock-ville (MD): FDA 2006Google Scholar
  9. 9.
    Breckenridge A, Orme M, Wesseling H, et al. Pharmaco-kinetics and pharmacodynamics of the enantiomers of warfarin in men. Clin Pharmacol Ther 1974; 15: 424–30PubMedGoogle Scholar
  10. 10.
    Kaminsky LS, Zhang ZY. Human P450 metabolism of warfarin. Pharmacol Ther 1997; 73: 67–74PubMedCrossRefGoogle Scholar
  11. 11.
    Tamazaki H, Shimada T. Human liver cytochrome P450 enzymes involved in the 7-hydroxylation of R- and S- warfarin enantiomers. Biochem Pharmacol 1997; 54:1195–203CrossRefGoogle Scholar
  12. 12.
    Takahashi H, Echizen H. Pharmacogenetics of CYP2C9 and interindividual variability in anticoagulant response to warfarin. Pharmacogenomics 2003; 3: 202–14CrossRefGoogle Scholar
  13. 13.
    Aithal GP, Day CP, Kesteven PJ, et al. Association of polymorphisms in the cytochrome P450 CYP2C9 with warfarin dose requirement and risk of bleeding complications. Lancet 1999; 353: 717–9PubMedCrossRefGoogle Scholar
  14. 14.
    Kumar V, Brundage RC, Oetting WS, et al. Differential genotype dependent inhibition of CYP2C9 in humans. Drug Metab Dispos 2008; 36: 1242–8PubMedCrossRefGoogle Scholar
  15. 15.
    U.S. Food and Drug Administration (FDA). Guidance for industry: food-effect bioavailability and fed bioequivalence studies. Rockville (MD): FDA 2002Google Scholar
  16. 16.
    Benet L. Relevance of pharmacokinetics in narrow therapeutic index drugs. Transplant Proc 1999; 31: 1642–4PubMedCrossRefGoogle Scholar
  17. 17.
    He YL, Sabo R, Riviere GJ, et al. Effect of the novel oral dipeptidyl peptidase IV inhibitor vildagliptin on the pharmacokinetics and pharmacodynamics of warfarin in healthy subjects. Curr Med Res Opin 2007; 5: 1131–8CrossRefGoogle Scholar
  18. 18.
    Common Toxicity Criteria for Adverse Events v 3.0 (CTCAE) [online]. Available from URL: http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/ctcaev3.pdf. [Accessed 2010 Nov 19]
  19. 19.
    Obach RS, Walsky RL, Venkatakrishnan K, et al. The utility of in vitro cytochrome P450 inhibition data in the prediction of drug-drug interactions. J Pharmacol Exp Ther 2006; 316: 336–48PubMedCrossRefGoogle Scholar
  20. 20.
    Yacobi A, Levy G. Protein binding of warfarin enantiomers in serum of humans and rats. J Pharmacokinet Biopharm 1977; 5: 123–31PubMedCrossRefGoogle Scholar
  21. 21.
    Bjornsson TD, Meffin PJ, Swezey S, et al. Clofibrate displaces warfarin from plasma proteins in man: an example of a pure displacement interaction. J Pharmacol Exp Ther 1979; 210: 316–21PubMedGoogle Scholar
  22. 22.
    Diana FJ, Veronich K, Kapoor AL. Binding of nonsteroidal anti-inflammatory agents and their effect on binding of racemic warfarin and its enantiomers to human serum albumin. J Pharm Sci 1989; 78: 195–9PubMedCrossRefGoogle Scholar
  23. 23.
    Serlin MJ, Mossman S, Sibeon RG, et al. Interaction between diflunisal and warfarin. Clin Pharmacol Ther 1980; 28: 493–8PubMedCrossRefGoogle Scholar
  24. 24.
    Sands CD, Chan ES, Welty TE. Revisiting the significance of warfarin protein-binding displacement interactions. Ann Pharmacother 2002 Oct; 36: 1642–4PubMedCrossRefGoogle Scholar
  25. 25.
    Benet LZ, Hoener B. Changes in plasma protein binding have little clinical relevance. Clin Pharmacol Ther 2002; 71:115–21PubMedCrossRefGoogle Scholar
  26. 26.
    Rowland M, Tozer TN. Clinical pharmacokinetics: concepts and applications. 3rd ed. New York: Lippincott Williams & Wilkins, 1995Google Scholar

Copyright information

© Adis Data Information BV 2011

Authors and Affiliations

  • Ophelia Q.P. Yin
    • 1
  • Neil Gallagher
    • 2
  • Deirdre Fischer
    • 1
  • Lily Zhao
    • 1
  • Wei Zhou
    • 3
  • Elisabeth Leroy
    • 3
  • Georg Golor
    • 4
  • Horst Schran
    • 1
  1. 1.Novartis Pharmaceuticals CorporationFlorham ParkUSA
  2. 2.Novartis Pharma AGBaselSwitzerland
  3. 3.Novartis Institutes for Biomedical ResearchEast HanoverUSA
  4. 4.PAREXEL International GmbHBerlinGermany

Personalised recommendations