title: Voriconazole plasma concentrations in immunocompromised pediatric patients vary by CYP2C19 diplotypes.
abstract: OBJECTIVE
  Our objective was to describe the association between voriconazole concentrations and CYP2C19 diplotypes in pediatric cancer patients, including children homozygous for the CYP2C19*17 gain-of-function allele.
  
  
  METHODS
  A linear mixed effect model compared voriconazole dose-corrected trough concentrations (n = 142) among CYP2C19 diplotypes in 33 patients (aged 1-19 years). Voriconazole pharmacokinetics was described by a two-compartment model with Michaelis-Menten elimination.
  
  
  RESULTS
  Age (p = 0.05) and CYP2C19 diplotype (p = 0.002) were associated with voriconazole concentrations. CYP2C19*17 homozygotes never attained therapeutic concentrations, and had lower dose-corrected voriconazole concentrations (median 0.01 μg/ml/mg/kg; p = 0.02) than CYP2C19*1 homozygotes (median 0.07 μg/ml/mg/kg). Modeling indicates that higher doses may produce therapeutic concentrations in younger children and in those with a CYP2C19*17/*17 diplotype.
  
  
  CONCLUSIONS
  Younger age and the presence of CYP2C19 gain-of-function alleles were associated with subtherapeutic voriconazole concentrations. Starting doses based on age and CYP2C19 status could increase the number of patients achieving therapeutic voriconazole exposure.
authors.affiliation: Department of Pharmaceutical Sciences, St Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA.
authors.forename: J Kevin
authors.initials: JK
authors.lastname: Hicks
authors.forename: Kristine R
authors.initials: KR
authors.lastname: Crews
authors.forename: Patricia
authors.initials: P
authors.lastname: Flynn
authors.forename: Cyrine E
authors.initials: CE
authors.lastname: Haidar
authors.forename: Calvin C
authors.initials: CC
authors.lastname: Daniels
authors.forename: Wenjian
authors.initials: W
authors.lastname: Yang
authors.forename: John C
authors.initials: JC
authors.lastname: Panetta
authors.forename: Deqing
authors.initials: D
authors.lastname: Pei
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Scott
authors.forename: Alejandro R
authors.initials: AR
authors.lastname: Molinelli
authors.forename: Ulrich
authors.initials: U
authors.lastname: Broeckel
authors.forename: Deepa
authors.initials: D
authors.lastname: Bhojwani
authors.forename: William E
authors.initials: WE
authors.lastname: Evans
authors.forename: Mary V
authors.initials: MV
authors.lastname: Relling
mesh_terms: D000293:Adolescent; D000328:Adult; D000483:Alleles; D002648:Child; D002675:Child, Preschool; D065731:Cytochrome P-450 CYP2C19 / Q000097:blood / Q000235:genetics*; D005260:Female; D005838:Genotype; D006239:Haplotypes; D006720:Homozygote; D006801:Humans; D007223:Infant; D008297:Male; D010597:Pharmacogenetics; D065819:Voriconazole / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use
chemical_list: C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D065819:Voriconazole
keywords: CYP2C19; antifungals; personalized medicine; pharmacogenetics; voriconazole
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