title: Safety of posaconazole and sirolimus coadministration in allogeneic hematopoietic stem cell transplants.
abstract: Sirolimus is used in allogeneic hematopoietic stem cell transplants (HSCTs) for prevention and treatment of graft-versus-host disease (GVHD). Posaconazole is used in this population for invasive fungal disease (IFD) prophylaxis and treatment. As posaconazole strongly inhibits CYP3A4, concurrent administration of sirolimus, a CYP3A4 substrate, and posaconazole has been reported to increase sirolimus drug exposure substantially. Coadministration of posaconazole and sirolimus is contraindicated by the manufacturer of posaconazole. We identified 15 patients who underwent HSCTs at our institution receiving a steady-state dose of sirolimus who subsequently started posaconazole therapy from January 2006 to March 2009. We recorded baseline characteristics, drug administration details, and potential adverse effects related to either drug. All patients underwent HSCTs for treatment of hematologic malignancy. All patients were initially prescribed sirolimus for GVHD prophylaxis and continued therapy after developing GVHD. Twelve patients (80%) received posaconazole for IFD prophylaxis in the setting of GVHD and 3 (20%) for IFD treatment. Patients received sirolimus and posaconazole concurrently for a median of 78 days (interquartile range [IQR] 25-177; range, 6-503). The median daily dose of sirolimus (2 mg/day) before initiation of posaconazole was reduced 50% to a median daily dose of 1 mg/day at steady state. Six patients experienced sirolimus trough levels greater than 12 ng/mL during coadministration, but only 1 patient experienced an adverse event potentially associated with sirolimus exposure during the first month of coadministration. This patient's sirolimus dose was empirically reduced by only 30% on posaconazole initiation. Concurrent sirolimus and posaconazole use seems to be well tolerated with a 33% to 50% empiric sirolimus dose reduction and close monitoring of serum sirolimus trough levels at the time of posaconazole initiation.
authors.affiliation: Division of Infectious Diseases, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA. dwkubiak@partners.org
authors.forename: David W
authors.initials: DW
authors.lastname: Kubiak
authors.forename: Sophia
authors.initials: S
authors.lastname: Koo
authors.forename: Sarah P
authors.initials: SP
authors.lastname: Hammond
authors.forename: Philippe
authors.initials: P
authors.lastname: Armand
authors.forename: Lindsey R
authors.initials: LR
authors.lastname: Baden
authors.forename: Joseph H
authors.initials: JH
authors.lastname: Antin
authors.forename: Francisco M
authors.initials: FM
authors.lastname: Marty
mesh_terms: D000328:Adult; D000935:Antifungal Agents / Q000627:therapeutic use*; D004334:Drug Administration Schedule; D054796:Drug Dosage Calculations; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D005260:Female; D006086:Graft vs Host Disease / Q000276:immunology / Q000628:therapy; D019337:Hematologic Neoplasms / Q000150:complications / Q000276:immunology / Q000628:therapy*; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D009181:Mycoses / Q000150:complications / Q000276:immunology / Q000628:therapy*; D020123:Sirolimus / Q000627:therapeutic use*; D014184:Transplantation, Homologous; D014230:Triazoles / Q000627:therapeutic use*
chemical_list: D000935:Antifungal Agents; D007166:Immunosuppressive Agents; D014230:Triazoles; C101425:posaconazole; D020123:Sirolimus