Medical College of Wisconsin
CTSICores SearchResearch InformaticsREDCap

Voriconazole plasma concentrations in immunocompromised pediatric patients vary by CYP2C19 diplotypes. Pharmacogenomics 2014 Jun;15(8):1065-78

Date

08/02/2014

Pubmed ID

25084200

Pubmed Central ID

PMC4155516

DOI

10.2217/pgs.14.53

Scopus ID

2-s2.0-84905446128 (requires institutional sign-in at Scopus site)   53 Citations

Abstract

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 MV

Author

Ulrich Broeckel MD Chief, Center Associate Director, Professor in the Pediatrics department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Adolescent
Adult
Alleles
Child
Child, Preschool
Cytochrome P-450 CYP2C19
Female
Genotype
Haplotypes
Homozygote
Humans
Infant
Male
Pharmacogenetics
Voriconazole