Warfarin-fluconazole. III. A rational approach to management of a metabolically based drug interaction

The results of studies of the effect of fluconazole on cytochrome P450 (P450) 2C9 activity in vivo and in vitro are used to develop an approach to the safe management of the warfarin-fluconazole drug interaction. This approach begins with a determination of an in vitro Ki value (22 microM), which may be used to relate fluconazole plasma concentrations to inhibitory effect on P4502C9 activity and (S)-warfarin half-life. A means for adding fluconazole to a therapeutic regimen of warfarin is proposed that involves a stepped reduction of the warfarin dose over 5 days to a final target daily dose that is determined by the fluconazole dose level. The effect of interindividual pharmacokinetic variability on outcome quality is explored in simulation studies that indicate that a stepped-dose reduction schedule will be superior to a one-time dose reduction. The in vivo K, was found to predict accurately the magnitude of the fluconazole interaction study with another P4502C9 substrate tolbutamide.