Safety of voriconazole and sirolimus coadministration after allogeneic hematopoietic SCT Journal Article

Authors: Ceberio, I.; Dai, K.; Devlin, S. M.; Barker, J. N.; Castro-Malaspina, H.; Goldberg, J. D.; Giralt, S.; Adel, N. G.; Perales, M. A.
Article 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. © 2015 Macmillan Publishers Limited.
Keywords: adult; aged; major clinical study; drug tolerability; dose response; drug dose reduction; drug safety; drug withdrawal; unspecified side effect; methotrexate; low drug dose; liver toxicity; nephrotoxicity; steady state; qt prolongation; creatinine; creatinine blood level; patient identification; rash; hematologic malignancy; graft versus host reaction; reduced intensity conditioning; allogeneic hematopoietic stem cell transplantation; drug monitoring; drug blood level; graft rejection; drug substitution; tacrolimus; visual disorder; thrombotic thrombocytopenic purpura; rapamycin; mycosis; voriconazole; liver venoocclusive disease; human; male; female; priority journal; article
Journal Title: Bone Marrow Transplantation
Volume: 50
Issue: 3
ISSN: 0268-3369
Publisher: Nature Publishing Group  
Date Published: 2015-03-01
Start Page: 438
End Page: 443
Language: English
DOI: 10.1038/bmt.2014.286
PROVIDER: scopus
PMCID: PMC4379043
PUBMED: 25599164
Notes: Export Date: 2 September 2015 -- Source: Scopus
Citation Impact
MSK Authors
  1. Sergio Andres Giralt
    619 Giralt
  2. Miguel-Angel Perales
    465 Perales
  3. Juliet N Barker
    253 Barker
  4. Nelly G Adel
    43 Adel
  5. Izaskun Ceberio
    10 Ceberio
  6. Sean McCarthy Devlin
    356 Devlin
  7. Kefei Dai
    3 Dai