title: Voriconazole therapeutic drug monitoring: retrospective cohort study of the relationship to clinical outcomes and adverse events.
abstract: BACKGROUND
  Voriconazole is approved for treatment of invasive aspergillosis and other invasive fungal infections, but the role for therapeutic drug monitoring (TDM) is not clear.
  
  
  METHODS
  We performed a retrospective cohort study of patients at the University of Washington Medical Center and Fred Hutchinson Cancer Research Center from 2007-2009. We compared the effect of therapeutic levels on clinical outcomes and evaluated the relationship between drug levels and adverse events.
  
  
  RESULTS
  A total of 108 patients had voriconazole TDM performed, of whom 84 (77.8%) had a hematologic malignancy and 47 (43.5%) had undergone hematopoietic stem cell transplantation. The primary reasons for treatment were presumed pulmonary aspergillosis (n = 83, 76.8%), other invasive mould infections (n = 13, 12.0%) and candidiasis (n = 9, 8.3%). There was a high degree of variability in voriconazole drug levels among patients (r2 = 0.01; range, <0.10 - 20 mg/L). Of the 46 patients with proven or probable invasive fungal disease, 25 (54.3%) achieved partial or complete response to therapy. There was no significant relationship between therapeutic drug levels and achievement of complete or partial response at 12 weeks (OR 0.29, 95% CI: 0.05-1.34) or radiologic response (OR 1.46, 95% CI: 0.32-7.83). Overall, 45 (41.7%) patients experienced adverse events. Voriconazole levels > 5.5 mg/L were not associated with increased incidence of encephalopathy (OR 3.08, 95% CI 0.79-11.0) or hepatotoxicity (OR 2.45, 95% CI 0.49-10.1).
  
  
  CONCLUSIONS
  Voriconazole therapeutic drug levels were not associated with improvement in clinical outcomes among patients with proven or probable invasive fungal disease. We also did not find an association between supratherapeutic drug levels and hepatoxicity or encephalopathy. It is possible that the utility of voriconazole therapeutic drug monitoring to improve clinical efficacy or decrease adverse events may be limited to a subset of high-risk patients.
authors: Helen Y
authors: HY
authors: Chu
authors: Rupali
authors: R
authors: Jain
authors: Hu
authors: H
authors: Xie
authors: Paul
authors: P
authors: Pottinger
authors: David N
authors: DN
authors: Fredricks
mesh_terms: D000328:Adult; D000935:Antifungal Agents / Q000008:administration & dosage / Q000009:adverse effects*; D001928:Brain Diseases, Metabolic / Q000175:diagnosis / Q000473:pathology; D002177:Candidiasis / Q000150:complications / Q000188:drug therapy* / Q000473:pathology; D004334:Drug Administration Schedule; D016903:Drug Monitoring; D005260:Female; D019337:Hematologic Neoplasms / Q000150:complications / Q000188:drug therapy* / Q000473:pathology; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D008099:Liver / Q000187:drug effects; D008297:Male; D008875:Middle Aged; D055732:Pulmonary Aspergillosis / Q000150:complications / Q000188:drug therapy* / Q000473:pathology; D011743:Pyrimidines / Q000008:administration & dosage / Q000009:adverse effects*; D012189:Retrospective Studies; D016896:Treatment Outcome; D014230:Triazoles / Q000008:administration & dosage / Q000009:adverse effects*; D065819:Voriconazole
chemical_list: D000935:Antifungal Agents; D011743:Pyrimidines; D014230:Triazoles; D065819:Voriconazole