title: Safety of voriconazole and sirolimus coadministration after allogeneic hematopoietic SCT.
abstract: Antifungal prophylaxis with azoles is considered standard in allogeneic hematopoietic SCT (allo-HSCT). Although sirolimus is being used increasingly for the prevention of GVHD, it is a substrate of CYP3A4, which is inhibited by voriconazole, and concurrent administration can lead to significantly increased exposure to sirolimus. We identified 67 patients with hematologic malignancies who underwent allo-HSCT with sirolimus, tacrolimus and low-dose MTX and received concomitant voriconazole prophylaxis from April 2008 to June 2011. All patients underwent a non-myeloablative or reduced-intensity conditioned allo-HSCT. Patients received sirolimus and voriconazole concurrently for a median of 113 days. The median daily dose reduction of sirolimus at the start of coadministration was 90%. The median serum sirolimus trough levels before and at steady state of coadministration were 5.8 ng/mL (range: 0-47.6) and 6.1 ng/mL (range: 1-14.2) (P=0.45), respectively. One patient with an average sirolimus level of 6 ng/mL developed sirolimus-related thrombotic microangiopathy that resolved after sirolimus discontinuation. No sinusoidal obstructive syndrome was reported. Seventeen patients (25%) prematurely discontinued voriconazole because of the adverse events. Only two patients (3%) presented with possible invasive fungal infections at day 100. We demonstrate that sirolimus and voriconazole coadministration with an empiric 90% sirolimus dose reduction and close monitoring of sirolimus trough levels is safe and well tolerated.
authors.affiliation: 1] Adult Bone Marrow Transplantation Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA [2] Department of Hematology, Hospital Universitario Donostia, Donostia, Spain.
authors.forename: I
authors.initials: I
authors.lastname: Ceberio
authors.affiliation: Pharmacy Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: K
authors.initials: K
authors.lastname: Dai
authors.affiliation: Department of Biostatistics and Epidemiology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: S M
authors.initials: SM
authors.lastname: Devlin
authors.affiliation: 1] Adult Bone Marrow Transplantation Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA [2] Weill Cornell Medical College, New York, NY, USA.
authors.forename: J N
authors.initials: JN
authors.lastname: Barker
authors.affiliation: 1] Adult Bone Marrow Transplantation Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA [2] Weill Cornell Medical College, New York, NY, USA.
authors.forename: H
authors.initials: H
authors.lastname: Castro-Malaspina
authors.affiliation: 1] Adult Bone Marrow Transplantation Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA [2] Weill Cornell Medical College, New York, NY, USA.
authors.forename: J D
authors.initials: JD
authors.lastname: Goldberg
authors.affiliation: 1] Adult Bone Marrow Transplantation Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA [2] Weill Cornell Medical College, New York, NY, USA.
authors.forename: S
authors.initials: S
authors.lastname: Giralt
authors.affiliation: Pharmacy Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: N G
authors.initials: NG
authors.lastname: Adel
authors.affiliation: 1] Adult Bone Marrow Transplantation Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA [2] Weill Cornell Medical College, New York, NY, USA.
authors.forename: M-A
authors.initials: MA
authors.lastname: Perales
mesh_terms: D000328:Adult; D000368:Aged; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage; D000935:Antifungal Agents / Q000008:administration & dosage; D004347:Drug Interactions; D005260:Female; D019337:Hematologic Neoplasms / Q000628:therapy*; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods*; D006801:Humans; D008297:Male; D008875:Middle Aged; D020123:Sirolimus / Q000008:administration & dosage* / Q000009:adverse effects; D014184:Transplantation, Homologous; D065819:Voriconazole / Q000008:administration & dosage* / Q000009:adverse effects; D055815:Young Adult
chemical_list: D000903:Antibiotics, Antineoplastic; D000935:Antifungal Agents; D065819:Voriconazole; D020123:Sirolimus