Drug interaction of (S)-warfarin, and not (R)-warfarin, with itraconazole in a hematopoietic stem cell transplant recipient

BackgroundItraconazole is a potent inhibitor of CYP3A4 and P-glycoprotein, but not CYP2C9. Herein, we report a case study in which the plasma concentration of the CYP2C9 substrate (S)-warfarin, and not the CYP3A4 substrate (R)-warfarin, increased with itraconazole coadministration.CaseA 67-y-old man received an allogenic bone marrow transplant for acute lymphoid leukemia. He was taking oral itraconazole (200 mg/day) and was started on a warfarin dose of 2.0 mg/day. The plasma concentrations of (S)- and (R)-warfarin 3 days after starting warfarin administration were 216 and 556 ng/mL, respectively (INR 0.98), and after 10 days, the concentrations were 763 and 545 ng/mL, respectively (INR 2.43). On day 11 after withdrawal of itraconazole, the concentrations of (S)- and (R)-warfarin were 341 and 605 ng/mL, respectively (INR 1.38). The concentration of (R)-warfarin was not affected by itraconazole; however, the final (S)-warfarin concentration had increased 7.3-fold. The (S)-warfarin/(S)-7-hydroxywarfarin ratio decreased to 2.45 from 8.40 after discontinuation of itraconazole. The permeability of warfarin enantiomers across Caco-2 cells was not influenced by itraconazole and showed no difference between enantiomers.ConclusionsCareful INR monitoring is necessary for warfarin co-administration with itraconazole. Further examination is necessary to elucidate mechanisms of the interaction between warfarin and itraconazole.

► Co-administration with itraconazole resulted in a higher plasma concentration of (S)-warfarin than (R)-warfarin.
► (S)-Warfarin concentration was increased 7.3-fold with itraconazole co-administration.
► Permeability of warfarin enantiomers across Caco-2 cells was not influenced by itraconazole.
► Continued INR monitoring after 7 days of warfarin co-administration with itraconazole should be performed.