Fluconazole Coadministration Concurrent with Cyclophosphamide Conditioning May Reduce Regimen-Related Toxicity Postmyeloablative Hematopoietic Cell Transplantation

Abstract 

In a previous study comparing fluconazole and itraconazole administered as antifungal prophylaxis in hematopoietic cell transplant (HCT) recipients, we found that fluconazole administration concurrent with cyclophosphamide (CY)-based conditioning was associated with fewer early toxicities compared to itraconazole. Fluconazole inhibits cytochrome P450 2C9, which is involved with the activation of CY, and so might provide protection from CY-related toxicities. To investigate this further, we compared CY and CY-metabolite data from patients who received fluconazole (n = 56) concurrent with CY-containing conditioning and in patients who did not (n = 17). The fluconazole group had greater exposure to CY, and lower peak serum concentration of CY-metabolite 4-hydroxycyclophosphamide. In a separate cohort, we examined outcomes in patients randomized to receive either fluconazole (n = 152) or placebo (n = 147) concurrent with CY-containing conditioning in a prior randomized trial. Patients who received fluconazole experienced less hepatic and renal toxicity, and had lower mortality. No difference in relapsed malignancy was apparent. These data support the hypothesis that fluconazole, when coadministered with CY, decreases CY-related toxicities by inhibiting cytochrome P450 2C9 metabolism.

Key Words: Fluconazole metabolism, Cyclophosphamide metabolism