title: Clinical impact and management of fluconazole discontinuation on sirolimus levels in bone marrow transplant patients.
abstract: Sirolimus, an immunosuppressant, is indicated post-allogeneic stem cell transplant to reduce the risk of graft-versus-host-disease. Sirolimus is metabolized by cytochrome P450 3A4 and is a substrate of the P-glycoprotein (P-gp) drug efflux pump. Interactions with known inhibitors of the CYP3A4 enzyme and P-glycoprotein, such as fluconazole, are anticipated. Co-administration of fluconazole leads to an increase in sirolimus blood concentrations due to an inhibition of metabolism. The discontinuation of fluconazole will likely result in a decline in sirolimus blood concentrations, leaving patients at risk of graft-versus-host-disease. We report on three patients managed by the Hematology, Oncology Blood and Marrow Transplant Program at the Alberta Children's Hospital. The discontinuation of fluconazole showed a marked reduction in sirolimus trough levels, requiring >200% increase in sirolimus dose to achieve therapeutic levels.
authors.affiliation: 1 Skaggs School of Pharmacy, University of Colorado, Aurora, CO, USA.
authors.forename: Edith
authors.initials: E
authors.lastname: Nwaroh
authors.affiliation: 2 Pharmacy Department, Alberta Children's Hospital, Alberta Health Services, Calgary, AB, Canada.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Jupp
authors.affiliation: 2 Pharmacy Department, Alberta Children's Hospital, Alberta Health Services, Calgary, AB, Canada.
authors.forename: Esther
authors.initials: E
authors.lastname: Jadusingh
authors.affiliation: 3 Department of Oncology, Section of Paediatric Oncology/Transplant, Calgary, AB, Canada.|4 Department of Paediatrics, Section of Paediatric Oncology/Transplant, Calgary, AB, Canada.
authors.forename: Gregory
authors.initials: G
authors.lastname: Guilcher
mesh_terms: D000293:Adolescent; D000416:Alberta; D016026:Bone Marrow Transplantation / Q000009:adverse effects / Q000639:trends*; D002648:Child; D019468:Disease Management; D004347:Drug Interactions / Q000502:physiology; D005260:Female; D015725:Fluconazole / Q000097:blood* / Q000627:therapeutic use; D006086:Graft vs Host Disease / Q000097:blood* / Q000188:drug therapy; D006801:Humans; D007166:Immunosuppressive Agents / Q000097:blood* / Q000627:therapeutic use; D008297:Male; D020123:Sirolimus / Q000097:blood* / Q000627:therapeutic use
chemical_list: D007166:Immunosuppressive Agents; D015725:Fluconazole; D020123:Sirolimus
keywords: Bone marrow transplant; drug interaction; fluconazole; sick cell anemia; sirolimus