ABSTRACT
Aim: This prospective
study aims to investigate the factors influencing voriconazole
trough concentration
(Cmin), develop a population pharmacokinetics (PPK)
model and recommend an appropriate voriconazole dosing regimen for
children with hematological malignancies.
Methods: Prospectively enrolled a total of 70 children aged
<18 years and 149 samples. The factors influencing
voriconazole Cmin were analyzed by univariate analysis
and multiple linear regression analysis. Nonlinear mixed effects
modeling (NONMEM) was applied to establish the PPK model. Dosage
simulation based on albumin (ALB) levels and CYP2C19 genotype.
Results : Multiple linear regression results demonstrated that
route of administration, ALB and concomitant administration with
glucocorticoid (GLU) and proton pump inhibitors (PPIs) were significant
factors of voriconazole Cmin. A one-compartment model
could best describe the pharmacokinetics of voriconazole. The extensive
metabolizers (EM), ALB were significant covariates of clearance (CL).
The typical value of CL, the volume of distribution (V) and oral
bioavailability (F) were 1.52 L/h, 35.7 L and 0.909, respectively. The
recommended dosing regimens for EM patients with ALB level of
20.0~35.0 g/L, 35.1~45.0 g/L and
45.1~55.0 g/L were4, 8 and 12 mg/kg intravenously or
orally twice daily, respectively, and were 2, 4 and 7 mg/kg by
intravenous or oral administration twice daily for non-EM.
Conclusion : We found that route of administration, ALB and
co-administration of GLU and PPI had quantitative relationships with
voriconazole Cmin. The combination of CYP2C19 genotype
and ALB levels to determine the initial dosing regimen of voriconazole
could provide a reference for individualized treatment in children with
hematological malignancies.