title: Impact of the CYP2C19 genotype on voriconazole exposure in adults with invasive fungal infections.
abstract: Voriconazole, a first-line agent for the treatment of invasive fungal infections (IFIs), is metabolized by CYP2C19. A significant proportion of patients fail to achieve therapeutic trough concentrations with standard weight-based voriconazole dosing, placing them at increased risk for treatment failure, which can be life threatening. We sought to test the association between the CYP2C19 genotype and subtherapeutic voriconazole concentrations in adults with IFIs.
  
  
  
  Adults receiving weight-based voriconazole dosing for the treatment of IFIs were genotyped for the CYP2C19*2, *3, and *17 polymorphisms, and CYP2C19 metabolizer phenotypes were inferred. Steady-state voriconazole trough plasma concentrations and the prevalence of subtherapeutic troughs (<2 mg/l) were compared between patients with the CYP2C19*17/*17 (ultrarapid metabolizer, UM) or *1/*17 (rapid metabolizer, RM) genotype versus those with other genotypes. Logistic regression, adjusting for clinical factors, was performed to estimate the odds of subtherapeutic concentrations.
  
  
  
  Of 70 patients included (mean age 52.5±18 years), 39% were RMs or UMs. Compared with patients with the other phenotypes, RMs/UMs had a lower steady-state trough concentration (4.26±2.2 vs. 2.86±2.3, P=0.0093) and a higher prevalence of subtherapeutic troughs (16 vs. 52%, P=0.0028), with an odds ratio of 5.6 (95% confidence interval: 1.64-19.24, P=0.0044).
  
  
  
  Our findings indicate that adults with the CYP2C19 RM or UM phenotype are more likely to have subtherapeutic concentrations with weight-based voriconazole dosing. These results corroborate previous findings in children and support the potential clinical utility of CYP2C19 genotype-guided voriconazole dosing to avoid underexposure in RMs and UMs.
authors.affiliation: aDepartment of Pharmacotherapy and Translational Research bCenter for Pharmacogenomics, College of Pharmacy, University of Florida cUniversity of Florida Health Shands Hospital, Gainesville dDepartment of Pharmaceutics eCenter for Pharmacometrics and Systems Pharmacology, College of Pharmacy, University of Florida, Orlando fDepartment of Medicine, Division of Hematology and Oncology gDepartment of Medicine, Division of Cardiology, College of Medicine, University of Florida, Gainesville, Florida, USA.
authors.forename: Issam S
authors.initials: IS
authors.lastname: Hamadeh
authors.forename: Kenneth P
authors.initials: KP
authors.lastname: Klinker
authors.forename: Samuel J
authors.initials: SJ
authors.lastname: Borgert
authors.forename: Ashley I
authors.initials: AI
authors.lastname: Richards
authors.forename: Wenhui
authors.initials: W
authors.lastname: Li
authors.forename: Naveen
authors.initials: N
authors.lastname: Mangal
authors.forename: John W
authors.initials: JW
authors.lastname: Hiemenz
authors.forename: Stephan
authors.initials: S
authors.lastname: Schmidt
authors.forename: Taimour Y
authors.initials: TY
authors.lastname: Langaee
authors.forename: Charles A
authors.initials: CA
authors.lastname: Peloquin
authors.forename: Julie A
authors.initials: JA
authors.lastname: Johnson
authors.forename: Larisa H
authors.initials: LH
authors.lastname: Cavallari
mesh_terms: D000328:Adult; D000368:Aged; D000935:Antifungal Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D065731:Cytochrome P-450 CYP2C19 / Q000235:genetics*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005838:Genotype; D006801:Humans; D000072742:Invasive Fungal Infections / Q000188:drug therapy* / Q000235:genetics; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D000071184:Pharmacogenomic Variants; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D065819:Voriconazole / Q000008:administration & dosage* / Q000493:pharmacokinetics
chemical_list: D000935:Antifungal Agents; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D065819:Voriconazole