Voriconazole plasma concentrations in immunocompromised pediatric patients vary by CYP2C19 diplotypes. Pharmacogenomics 2014 Jun;15(8):1065-78
Date
08/02/2014Pubmed ID
25084200Pubmed Central ID
PMC4155516DOI
10.2217/pgs.14.53Scopus ID
2-s2.0-84905446128 (requires institutional sign-in at Scopus site) 53 CitationsAbstract
AIM: 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.
MATERIALS & 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.
CONCLUSION: 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.
Author List
Hicks JK, Crews KR, Flynn P, Haidar CE, Daniels CC, Yang W, Panetta JC, Pei D, Scott JR, Molinelli AR, Broeckel U, Bhojwani D, Evans WE, Relling MVAuthor
Ulrich Broeckel MD Chief, Center Associate Director, Professor in the Pediatrics department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AdolescentAdult
Alleles
Child
Child, Preschool
Cytochrome P-450 CYP2C19
Female
Genotype
Haplotypes
Homozygote
Humans
Infant
Male
Pharmacogenetics
Voriconazole