Effects of nilotinib on single-dose warfarin pharmacokinetics and pharmacodynamics: a randomized, single-blind, two-period crossover study in healthy subjects

Clin Drug Investig. 2011;31(3):169-79. doi: 10.2165/11538700-000000000-00000.


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 (C(max)) 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 C(max) was 1872 ± 560 ng/mL, which is comparable to steady-state C(max) 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.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Adult
  • Aged
  • Anticoagulants / adverse effects
  • Anticoagulants / pharmacokinetics
  • Anticoagulants / pharmacology
  • Area Under Curve
  • Aryl Hydrocarbon Hydroxylases / antagonists & inhibitors
  • Aryl Hydrocarbon Hydroxylases / genetics
  • Aryl Hydrocarbon Hydroxylases / metabolism*
  • Cross-Over Studies
  • Cytochrome P-450 CYP2C9
  • Drug Interactions
  • Female
  • Fusion Proteins, bcr-abl / antagonists & inhibitors
  • Genotype
  • Humans
  • International Normalized Ratio
  • Male
  • Middle Aged
  • Protein Kinase Inhibitors / adverse effects
  • Protein Kinase Inhibitors / pharmacology*
  • Protein-Tyrosine Kinases / antagonists & inhibitors
  • Prothrombin Time
  • Pyrimidines / adverse effects
  • Pyrimidines / pharmacology*
  • Single-Blind Method
  • Warfarin / adverse effects
  • Warfarin / pharmacokinetics*
  • Warfarin / pharmacology
  • Young Adult


  • 4-methyl-N-(3-(4-methylimidazol-1-yl)-5-(trifluoromethyl)phenyl)-3-((4-pyridin-3-ylpyrimidin-2-yl)amino)benzamide
  • Anticoagulants
  • Protein Kinase Inhibitors
  • Pyrimidines
  • Warfarin
  • CYP2C9 protein, human
  • Cytochrome P-450 CYP2C9
  • Aryl Hydrocarbon Hydroxylases
  • Protein-Tyrosine Kinases
  • Fusion Proteins, bcr-abl