title: Concurrent administration of sirolimus and voriconazole: a pilot study assessing safety and approaches to appropriate management.
abstract: OBJECTIVE
  To assess the use and safety of concurrent administration of voriconazole and sirolimus-which is contraindicated-and to determine approaches for appropriately managing patients who receive both drugs.
  
  
  METHODS
  Retrospective medical record review.
  
  
  METHODS
  University-affiliated medical center.
  
  
  METHODS
  Thirty-one cases in 23 inpatients who received at least one dose of voriconazole and sirolimus concomitantly within a 24-hour period.
  
  
  RESULTS
  Data on sirolimus and voriconazole indications, doses, routes, frequencies, and administration times; number of days of coadministration; and sirolimus dosage adjustments were collected. In addition, data on laboratory values, adverse events, sirolimus concentrations, and concomitant drugs, including cytochrome P450 (CYP) 3A isoenzyme and P-glycoprotein inhibitors and inducers, were collected for 7 days before, during, and for 14 days after coadministration. No cases of elevated sirolimus concentrations (>20 mg/ml) occurred in patients stabilized with voriconazole before starting low-dose sirolimus 0.5-1 mg/day, or in those stabilized with sirolimus 0.5-2 mg/day who had baseline sirolimus concentrations of 12 ng/ml or lower and whose sirolimus dose was decreased by 50% before the addition of voriconazole. In contrast, elevated sirolimus concentrations were experienced in patients receiving sirolimus doses of 4 mg/day or higher who had sirolimus concentrations of 12 ng/ml or higher and whose sirolimus dose was not decreased before addition of voriconazole. In a patient who received sirolimus with itraconazole, a strong CYP3A isoenzyme inhibitor, one case of only a minimal increase in the sirolimus concentration occurred after the addition of voriconazole.
  
  
  CONCLUSIONS
  Sirolimus and voriconazole can be safely coadministered as long as consideration is given to which agent the patient receives first, the sirolimus dosage, sirolimus concentrations, and concurrent disease states and CYP3A isoenzyme inhibitors. Sirolimus concentrations should be closely and routinely monitored before, during, and after coadministration of voriconazole and other CYP3A isoenzyme inhibitors. Based on the results of this pilot study, a protocol on the management of this drug combination will be implemented and prospectively evaluated for efficacy and safety.
authors.affiliation: Department of Pharmacy Services, University of Michigan Health System, Ann Arbor, Michigan, USA.
authors.forename: Dorothy
authors.initials: D
authors.lastname: Surowiec
authors.forename: Daryl D
authors.initials: DD
authors.lastname: DePestel
authors.forename: Peggy L
authors.initials: PL
authors.lastname: Carver
mesh_terms: D000935:Antifungal Agents / Q000009:adverse effects*; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D004347:Drug Interactions; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects*; D010865:Pilot Projects; D011743:Pyrimidines / Q000009:adverse effects*; D012189:Retrospective Studies; D020123:Sirolimus / Q000009:adverse effects* / Q000493:pharmacokinetics; D014230:Triazoles / Q000009:adverse effects*; D065819:Voriconazole
chemical_list: D000935:Antifungal Agents; D065607:Cytochrome P-450 Enzyme Inhibitors; D007166:Immunosuppressive Agents; D011743:Pyrimidines; D014230:Triazoles; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; D065819:Voriconazole; D020123:Sirolimus