title: Putting CYP2C19 genotyping to the test: utility of pharmacogenomic evaluation in a voriconazole-treated haematology cohort.
abstract: OBJECTIVE
  The clinical utility of pharmacogenomic testing in haematology patients with invasive fungal disease (IFD) receiving azole therapy has not been defined. We report our experience with CYP2C19 testing in haematological patients requiring voriconazole therapy for IFD.
  
  
  METHODS
  As a single-centre pilot study, 19 consecutive patients with a haematological malignancy undergoing active chemotherapy with a possible, probable or proven IFD requiring voriconazole therapy underwent CYP2C19 testing from 2013 to 2014. Baseline patient demographics, concurrent medications, voriconazole levels and IFD history were captured.
  
  
  RESULTS
  The median voriconazole levels for intermediate metabolizer (IM) (CYP2C19*2 or 3/*1 or 17), extensive metabolizer (EM) (CYP2C19*1/*1) and heterozygote ultrarapid metabolizer (HUM)/ultrarapid metabolizer (UM) (UM, CYP2C19*17/*17; HUM, CYP2C19*1/*17) patients were 5.23, 3.3 and 1.25 mg/L, respectively. Time to therapeutic voriconazole levels was longest in the IM group, whilst voriconazole levels <1 mg/L were only seen in UM, HUM and EM phenotypes. The highest rates of clinical toxicity were seen in the IM group (3/5, 60%).
  
  
  CONCLUSIONS
  Voriconazole exposure and toxicity was highest for IM and lowest for HUM/UM phenotypes. Time to therapeutic voriconazole level was longest in IM, whilst refractory subtherapeutic levels requiring CYP2C19 inhibition were only seen in the EM, HUM and UM phenotypes. CYP2C19 genotyping may predict those likely to have supratherapeutic or subtherapeutic levels and/or toxicity. Prospective evaluation of clinical pathways incorporating genotyping and voriconazole dose-titrating algorithms is required.
authors.affiliation: Department of Infectious Diseases, Peter MacCallum Cancer Centre, East Melbourne, VIC, Australia jason.trubiano@petermac.org.
authors.forename: J A
authors.initials: JA
authors.lastname: Trubiano
authors.affiliation: Department of Infectious Diseases, Peter MacCallum Cancer Centre, East Melbourne, VIC, Australia.
authors.forename: A
authors.initials: A
authors.lastname: Crowe
authors.affiliation: Department of Infectious Diseases, Peter MacCallum Cancer Centre, East Melbourne, VIC, Australia.
authors.forename: L J
authors.initials: LJ
authors.lastname: Worth
authors.affiliation: Department of Infectious Diseases, Peter MacCallum Cancer Centre, East Melbourne, VIC, Australia Victorian Infectious Diseases Service, Royal Melbourne Hospital, Parkville, VIC, Australia.
authors.forename: K A
authors.initials: KA
authors.lastname: Thursky
authors.affiliation: Department of Infectious Diseases, Peter MacCallum Cancer Centre, East Melbourne, VIC, Australia Victorian Infectious Diseases Service, Royal Melbourne Hospital, Parkville, VIC, Australia.
authors.forename: M A
authors.initials: MA
authors.lastname: Slavin
mesh_terms: D000368:Aged; D000935:Antifungal Agents / Q000009:adverse effects* / Q000627:therapeutic use*; D015331:Cohort Studies; D065731:Cytochrome P-450 CYP2C19 / Q000235:genetics*; D005260:Female; D060005:Genotyping Techniques; D019337:Hematologic Neoplasms / Q000150:complications; D006801:Humans; D008297:Male; D008875:Middle Aged; D009181:Mycoses / Q000188:drug therapy*; D010597:Pharmacogenetics / Q000379:methods; D010865:Pilot Projects; D016896:Treatment Outcome; D065819:Voriconazole / Q000009:adverse effects* / Q000627:therapeutic use*
chemical_list: D000935:Antifungal Agents; D065731:Cytochrome P-450 CYP2C19; D065819:Voriconazole
keywords: IFD; IFIs; invasive fungal disease; invasive fungal infections