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.
AIM: Our objective was to describe the association between voriconazole concentrations and CYP2C19 diplotypes in pediatric cancerpatients, 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.
Authors: Thomas J Walsh; Elias J Anaissie; David W Denning; Raoul Herbrecht; Dimitrios P Kontoyiannis; Kieren A Marr; Vicki A Morrison; Brahm H Segal; William J Steinbach; David A Stevens; Jo-Anne van Burik; John R Wingard; Thomas F Patterson Journal: Clin Infect Dis Date: 2008-02-01 Impact factor: 9.079
Authors: Stuart A Scott; Katrin Sangkuhl; Alan R Shuldiner; Jean-Sébastien Hulot; Caroline F Thorn; Russ B Altman; Teri E Klein Journal: Pharmacogenet Genomics Date: 2012-02 Impact factor: 2.089
Authors: Michael J Dolton; Gerd Mikus; Johanna Weiss; John E Ray; Andrew J McLachlan Journal: J Antimicrob Chemother Date: 2014-02-18 Impact factor: 5.790
Authors: Souzan B Yanni; Pieter P Annaert; Patrick Augustijns; Joseph G Ibrahim; Daniel K Benjamin; Dhiren R Thakker Journal: Drug Metab Dispos Date: 2010-01 Impact factor: 3.922
Authors: Aniwaa Owusu Obeng; Eric F Egelund; Abdullah Alsultan; Charles A Peloquin; Julie A Johnson Journal: Pharmacotherapy Date: 2014-02-07 Impact factor: 4.705
Authors: Brad Moriyama; Sameer Kadri; Stacey A Henning; Robert L Danner; Thomas J Walsh; Scott R Penzak Journal: Curr Fungal Infect Rep Date: 2015-04-16
Authors: Andreas H Groll; Georg Hempel; Silke Gastine; Thomas Lehrnbecher; Carsten Müller; Fedja Farowski; Peter Bader; Judith Ullmann-Moskovits; Oliver A Cornely Journal: Antimicrob Agents Chemother Date: 2017-12-21 Impact factor: 5.191
Authors: J Kevin Hicks; Rod E Quilitz; Rami S Komrokji; Timothy E Kubal; Jeffrey E Lancet; Yanina Pasikhova; Dahui Qin; Wonhee So; Gisela Caceres; Kerry Kelly; Yasmina S Salchert; Kevin Shahbazian; Farnoosh Abbas-Aghababazadeh; Brooke L Fridley; Ana P Velez; Howard L McLeod; John N Greene Journal: Clin Pharmacol Ther Date: 2019-11-01 Impact factor: 6.875
Authors: Takuto Takahashi; Angela R Smith; Pamala A Jacobson; James Fisher; Nathan T Rubin; Mark N Kirstein Journal: Antimicrob Agents Chemother Date: 2020-11-17 Impact factor: 5.191
Authors: Neil T Mason; Gillian C Bell; Rod E Quilitz; John N Greene; Howard L McLeod Journal: J Antimicrob Chemother Date: 2015-08-01 Impact factor: 5.790