title: 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.
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center and University of Washington, Seattle, Washington, USA.
authors.forename: Arlo
authors.initials: A
authors.lastname: Upton
authors.forename: Jeannine S
authors.initials: JS
authors.lastname: McCune
authors.forename: Katharine A
authors.initials: KA
authors.lastname: Kirby
authors.forename: Wendy
authors.initials: W
authors.lastname: Leisenring
authors.forename: George
authors.initials: G
authors.lastname: McDonald
authors.forename: Ami
authors.initials: A
authors.lastname: Batchelder
authors.forename: Kieren A
authors.initials: KA
authors.lastname: Marr
mesh_terms: D000935:Antifungal Agents / Q000009:adverse effects / Q000493:pharmacokinetics*; D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D056486:Chemical and Drug Induced Liver Injury; D015331:Cohort Studies; D003520:Cyclophosphamide / Q000009:adverse effects / Q000493:pharmacokinetics*; D065729:Cytochrome P-450 CYP2C9; D005260:Female; D015725:Fluconazole / Q000009:adverse effects / Q000493:pharmacokinetics*; D018380:Hematopoietic Stem Cell Transplantation / Q000401:mortality; D006801:Humans; D007674:Kidney Diseases / Q000139:chemically induced / Q000401:mortality / Q000517:prevention & control; D008107:Liver Diseases / Q000401:mortality / Q000517:prevention & control; D008297:Male; D009181:Mycoses / Q000517:prevention & control*; D019653:Myeloablative Agonists / Q000009:adverse effects / Q000493:pharmacokinetics*; D019172:Transplantation Conditioning / Q000401:mortality; D014184:Transplantation, Homologous
chemical_list: D000935:Antifungal Agents; D019653:Myeloablative Agonists; D003520:Cyclophosphamide; D015725:Fluconazole; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases