title: Dosing algorithm for concomitant administration of sirolimus, tacrolimus, and an azole after allogeneic hematopoietic stem cell transplantation.
abstract: BACKGROUND
  Allogeneic hematopoietic stem cell transplant patients are at risk of invasive fungal infections and prophylaxis with azole agents is common practice. The concomitant use of these agents with sirolimus and tacrolimus for the prevention of graft-versus-host disease may result in excessive immunosuppression or toxicity.
  
  
  METHODS
  This retrospective study identified hospitalized patients who underwent allogeneic hematopoietic stem cell transplantation between August 2009 and April 2011 at Rush University Medical Center. From this group, patients who underwent concomitant tacrolimus, sirolimus, and azole therapy were included for evaluation. The immunosuppression dosing in conjunction with azole use at discharge was analyzed to develop a dosing algorithm dependent on whether fluconazole, posaconazole, or voriconazole was used.
  
  
  RESULTS
  A total of 36 patients were screened for inclusion, of which 8 were excluded due to acute renal failure and/or hemolysis. The remaining patients were stratified by the azole they were concomitantly taking with tacrolimus and sirolimus. The fluconazole arm required the lowest magnitude of dose reductions, while voriconazole required the greatest.
  
  
  CONCLUSIONS
  Dose reductions of 50-75% for both sirolimus and tacrolimus, in combination with standard dosing of azole antifungal agents, were necessary to achieve therapeutic drug concentrations for immunosuppressants and potentially avoid toxicities.
authors.affiliation: Department of Pharmacy, Rush University Medical Center, Chicago, IL, USA gary_d_peksa@rush.edu.
authors.forename: Gary D
authors.initials: GD
authors.lastname: Peksa
authors.affiliation: Department of Pharmacy, Rush University Medical Center, Chicago, IL, USA.
authors.forename: Kathryn
authors.initials: K
authors.lastname: Schultz
authors.affiliation: Division of Hematology, Oncology and Stem Cell Transplant, Rush University Medical Center, Chicago, IL, USA.
authors.forename: Henry C
authors.initials: HC
authors.lastname: Fung
mesh_terms: D000328:Adult; D000368:Aged; D000465:Algorithms; D000935:Antifungal Agents / Q000008:administration & dosage* / Q000627:therapeutic use*; D001393:Azoles / Q000008:administration & dosage* / Q000627:therapeutic use*; D054796:Drug Dosage Calculations; D005260:Female; D015725:Fluconazole / Q000008:administration & dosage / Q000627:therapeutic use; D019337:Hematologic Neoplasms / Q000628:therapy; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods*; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage* / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D009181:Mycoses / Q000517:prevention & control; D012189:Retrospective Studies; D020123:Sirolimus / Q000008:administration & dosage*; D016559:Tacrolimus / Q000008:administration & dosage*; D014230:Triazoles / Q000008:administration & dosage / Q000627:therapeutic use; D065819:Voriconazole / Q000008:administration & dosage / Q000627:therapeutic use; D055815:Young Adult
chemical_list: D000935:Antifungal Agents; D001393:Azoles; D007166:Immunosuppressive Agents; D014230:Triazoles; C101425:posaconazole; D015725:Fluconazole; D065819:Voriconazole; D020123:Sirolimus; D016559:Tacrolimus
keywords: Sirolimus; azoles; dosing scheme; hematopoietic stem cell transplantation; interaction; tacrolimus