Clinical impact and management of fluconazole discontinuation on sirolimus levels in bone marrow transplant patients.

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.