title: Voriconazole-related severe adverse events: clinical application of therapeutic drug monitoring in Korean patients.
abstract: BACKGROUND
  Voriconazole is a triazole agent with excellent antifungal activity against Aspergillus species. However, despite its potential advantages, the occurrence of unpredictable toxicities might be critical in immunocompromised patients. The aim of this study was to analyze risk factors for voriconazole-related severe adverse events (SAEs).
  
  
  METHODS
  This prospective observational study was conducted in Korean patients with hematological malignancies and invasive aspergillosis on intravenous voriconazole therapy between June 2008 and April 2009.
  
  
  RESULTS
  Of the 25 patients enrolled, eight (32%) showed voriconazole-related SAEs, which included hepatotoxicities (n=5), cardiac tachyarrhythmias (n=2), and neurotoxicity (n=1). Sex, age, underlying hematological malignancies, voriconazole dose, the co-administration of a proton pump inhibitor, and CYP2C19 genotype were not found to be related to the occurrence of SAEs. However, trough plasma concentrations of voriconazole were found to be significantly higher in the patients with an SAE: median 6.32 mg/l (interquartile range (IQR) 2.86-9.71 mg/l) vs. median 2.15 mg/l (IQR 0.92-4.00 mg/l); p=0.011. Receiver operating characteristic curve analysis identified a cut-off trough concentration for SAEs of 5.83 mg/l (sensitivity 62.5% and specificity 94.1%). Furthermore, multivariate analysis showed that a trough concentration of ≥ 5.83mg/l was the only significant independent risk factor of an SAE.
  
  
  CONCLUSIONS
  This study shows that therapeutic drug monitoring is indicated in patients with a voriconazole-related SAE and that dose adjustment is required if the trough concentration of voriconazole exceeds 5.83 mg/l.
authors.affiliation: Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, South Korea.
authors.forename: Si-Hyun
authors.initials: SH
authors.lastname: Kim
authors.forename: Dong-Seok
authors.initials: DS
authors.lastname: Yim
authors.forename: Su-Mi
authors.initials: SM
authors.lastname: Choi
authors.forename: Jae-Cheol
authors.initials: JC
authors.lastname: Kwon
authors.forename: Seunghoon
authors.initials: S
authors.lastname: Han
authors.forename: Dong-Gun
authors.initials: DG
authors.lastname: Lee
authors.forename: Chulmin
authors.initials: C
authors.lastname: Park
authors.forename: Eun-Young
authors.initials: EY
authors.lastname: Kwon
authors.forename: Sun Hee
authors.initials: SH
authors.lastname: Park
authors.forename: Jung-Hyun
authors.initials: JH
authors.lastname: Choi
authors.forename: Jin-Hong
authors.initials: JH
authors.lastname: Yoo
mesh_terms: D000328:Adult; D000483:Alleles; D000935:Antifungal Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000097:blood / Q000627:therapeutic use; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics; D001228:Aspergillosis / Q000150:complications / Q000188:drug therapy* / Q000382:microbiology; D001230:Aspergillus / Q000187:drug effects*; D065731:Cytochrome P-450 CYP2C19; D016903:Drug Monitoring / Q000379:methods*; D005260:Female; D005838:Genotype; D019337:Hematologic Neoplasms / Q000150:complications* / Q000276:immunology; D006801:Humans; D016867:Immunocompromised Host; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D011743:Pyrimidines / Q000008:administration & dosage / Q000009:adverse effects* / Q000097:blood / Q000627:therapeutic use; D056910:Republic of Korea; D012307:Risk Factors; D014230:Triazoles / Q000008:administration & dosage / Q000009:adverse effects* / Q000097:blood / Q000627:therapeutic use; D065819:Voriconazole; D055815:Young Adult
chemical_list: D000935:Antifungal Agents; D011743:Pyrimidines; D014230:Triazoles; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D065819:Voriconazole