Effect of nilotinib on the pharmacokinetics and pharmacodynamics of warfarin

Abstract

7063 Background: Nilotinib, a highly selective and potent BCR-ABL tyrosine kinase inhibitor, is approved for the treatment of CML-CP and CML-AP in patients resistant or intolerant to prior therapy including imatinib. Nilotinib has shown competitive inhibition of CYP2C9 in vitro, but its effect on CYP2C9 activity in human is unknown. This study evaluated the effects of nilotinib on the pharmacokinetics (PK) and pharmacodynamics (PD) of warfarin, a sensitive CYP2C9 substrate, in healthy subjects. Methods: Twenty-four subjects (6F, 18M, age 21–65 years) were enrolled to receive a single oral 25 mg warfarin with either 800 mg nilotinib or matching placebo (administered 30 minutes after consumption of a high-fat meal) in a cross-over design. Serial blood samples were collected post-dose for determining nilotinib, S- and R-warfarin concentrations. Prothrombin time (PT) and international normalized ratio (INR) were determined as PD measures for warfarin. CYP2C9 genotyping was performed in all subjects using TaqMan assay. Results: Sixteen subjects were identified as CYP2C9 extensive metabolizers (EM) and 8 as intermediate metabolizers (IM), but none was poor metabolizer. PK parameters of S- and R-warfarin were found to be similar between two treatments (warfarin + nilotinib versus warfarin alone) for both EM and IM groups. The geometric mean ratios (90% CIs) for the Cmax and AUC0-∞ of S-warfarin in all subjects were 0.98 (0.95–1.02) and 1.03 (0.99–1.07), respectively, and for R-warfarin were 1.00 (0.96–1.04) and 1.02 (0.99–1.06) respectively. Mean ratios for the maximum value and AUC of PT were 1.00 (0.96–1.04) and 1.00 (0.98–1.02), respectively, and for INR were 1.00 (0.97–1.01) and 1.00 (0.99–1.01), respectively. Nilotinib Cmax was 1872±560 ng/mL, which is comparable to the mean steady-state Cmax in CML and GIST patients receiving 400 mg BID doses. Adverse effects observed following either treatment were generally consistent with the known safety profiles of both drugs, and there were no new safety issues observed. Conclusion: The study results demonstrate a lack of effect of nilotinib on the PK and PD of warfarin, suggesting nilotinib does not inhibit CYP2C9 activity in human subjects. These findings suggest that warfarin can be used with nilotinib concurrently without the risk of bleeding. [Table: see text]