title: Management of drug interaction between posaconazole and sirolimus in patients who undergo hematopoietic stem cell transplant.
abstract: OBJECTIVE
  To determine an appropriate empiric oral sirolimus dose adjustment when given concurrently with posaconazole oral suspension in patients who undergo hematopoietic stem cell transplant (HSCT).
  
  
  METHODS
  Retrospective cohort study.
  
  
  METHODS
  Comprehensive cancer center in the United States.
  
  
  METHODS
  Seventy five allogeneic HSCT patients who received posaconazole oral suspension and oral sirolimus concurrently between 2009 and 2011.
  
  
  RESULTS
  Sirolimus concentrations were recorded at baseline and for up to 28 days after posaconazole initiation. The sirolimus concentration/dose (C/D) ratio was determined for each sirolimus concentration obtained. Following analysis of patient data and based on the initial empiric sirolimus dose reduction, patients were stratified into two groups: ≥50% sirolimus dose reduction (Group 1) and <50% sirolimus dose reduction (Group 2). The mean sirolimus C/D ratio was 2.29 ng/mL/mg prior to posaconzole initiation. Coadministration of posaconazole and sirolimus resulted in an increase in the steady state sirolimus C/D ratio to 6.24 ng/mL/mg, which occurred approximately 17-20 days after initiation of posaconazole. The mean maximum sirolimus concentration was significantly higher in Group 2 compared to Group 1 (12.64 ng/mL vs. 9.24 ng/mL, p=0.001). Significantly more patients in Group 2 than Group 1 experienced at least one sirolimus concentration >15 ng/mL (27% vs. 2.6%, p=0.003).
  
  
  CONCLUSIONS
  Coadministration of posaconazole oral suspension with oral sirolimus increases the sirolimus C/D ratio by approximately 2.7-fold in HSCT patients. An initial empiric oral sirolimus dose reduction between 50% and 65% may be recommended for most clinically stable patients with close sirolimus concentration monitoring for at least 3 weeks following posaconazole initiation.
authors.affiliation: Department of Pharmacy, Sharp HealthCare, San Diego, California.
authors.forename: Eunah
authors.initials: E
authors.lastname: Cho
authors.affiliation: Department of Pharmacy, City of Hope National Medical Center, Duarte, California.
authors.forename: Holly
authors.initials: H
authors.lastname: Chan
authors.affiliation: College of Pharmacy, Western University of Health Sciences, Pomona, California.|Department of Pharmacy, St. Mary Medical Center, Long Beach, California.
authors.forename: Huan Mark
authors.initials: HM
authors.lastname: Nguyen
authors.affiliation: Department of Pharmacy, City of Hope National Medical Center, Duarte, California.
authors.forename: Sepideh
authors.initials: S
authors.lastname: Shayani
authors.affiliation: Department of Hematology and Hematopoietic Stem Cell Transplantation, City of Hope National Medical Center, Duarte, California.
authors.forename: Ryotaro
authors.initials: R
authors.lastname: Nakamura
authors.affiliation: Department of Pharmacy, City of Hope National Medical Center, Duarte, California.|College of Pharmacy, Western University of Health Sciences, Pomona, California.
authors.forename: Doreen
authors.initials: D
authors.lastname: Pon
mesh_terms: D000328:Adult; D000368:Aged; D000935:Antifungal Agents / Q000009:adverse effects*; D004347:Drug Interactions; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects* / Q000493:pharmacokinetics; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D020123:Sirolimus / Q000009:adverse effects* / Q000493:pharmacokinetics; D014230:Triazoles / Q000009:adverse effects*; D055815:Young Adult
chemical_list: D000935:Antifungal Agents; D007166:Immunosuppressive Agents; D014230:Triazoles; C101425:posaconazole; D020123:Sirolimus
keywords: cytochrome P450; drug interaction; hematopoietic stem cell transplant; p-glycoprotein; posaconazole; sirolimus