Model-Oriented Dose Optimization of Voriconazole in Critically Ill Children

This study aimed to employ a population pharmacokinetic (PK) model to optimize the dosing regimen of voriconazole (VRC) in children with a critical illness. A total of 99 children aged from 0.44 to 13.58 years were included in this study. The stability and predictive performance of the final model were evaluated by statistical and graphical methods. The optimal dosing regimen was proposed for children with different body weights, CYP2C19 phenotypes, and coadministrations with omeprazole. The PK of VRC was described by a two-compartment model with nonlinear Michaelis-Menten elimination. Body weight, CYP2C19 phenotype, and omeprazole were significant covariates on the maximum velocity of elimination (V_max), which had an estimated typical value of 18.13 mg · h^-1. Bayesian estimation suggested that the dose-normalized concentration and total exposure (peak concentration [C_max]/D, trough concentration [C_min]/D, and area under the concentration-time curve over 24 h [AUC₂₄]/D) were significantly different between extensive metabolizer (EM) patients and poor metabolizer (PM) patients. To achieve the target concentration early, two loading doses of 9 mg · kg^-1 of body weight every 12 h (q12h) were reliable for most children, whereas three loading doses of 6 to 7.5 mg · kg^-1 q8h were warranted for young children weighing ≤18 kg (except for PM patients). The maintenance doses decreased about 30 to 40% in PM patients compared to that in EM patients. For children aged <2 years, in EM patients, the maintenance dose could be as high as 9 mg · kg^-1. The maintenance dose of VRC was supposed to decrease slightly when coadministered with omeprazole. A population PK model of intravenous VRC for critically ill children has been successfully developed. It is necessary to adjust dosing regimens according to the CYP2C19 genotype. Optimal dosing regimens have been recommended based on the final model.