1. Introduction
Invasive fungal infection (IFI) is a serious fungal infection caused
mainly by Candida and Aspergillus.1 IFI dramatically
affects the prognosis of patients with hematologic malignancies, which
is one of the principal causes of death in hematologic
malignancies.2, 3 The Kobayashi et
al4 recorded that the survival rate of pediatric
patients with IFI is much lower than that of uninfected patients in
hematological malignancies.
Voriconazole is commonly used for the prevention and treatment of IFIs
as a triazole antifungal drug with broad-spectrum
activity.5 However, the metabolism of voriconazole in
vivo has the characteristics of non-linear
pharmacokinetics,6 and affected by multiple factors
such as weight, age, liver function, CYP2C19 genotype and drug
interaction, the intra- and interindividual variability in the plasma
concentrations is considerable.7-9 Besides, the poor
activity of hepatic drug enzymes in children makes it easier for drugs
to accumulate in the body, which leads to more obvious individual
differences of plasma concentrations and more complex pharmacokinetics
in children.10 It has been previously demonstrated
that there are significant differences in the pharmacokinetic profile of
voriconazole between children and adults.11Furthermore, pediatric patients with hematological malignancies are
vulnerable to myelosuppression and thrombocytopenia during chemotherapy,
which will affect the liver metabolism of voriconazole
pharmacokinetics.12 More importantly, the poor
metabolizer (PM) of CYP2C19 metabolic in Asians have a higher proportion
of distribution compared to other races13. These make
it impossible for children to be treated according to the recommended
regimens for adults or in Europe and the United States.
Population pharmacokinetics (PPK) analysis can assess the basic
characteristics of pharmacokinetics and identify the sources of inter-
and intra-individual variability14. Currently, the
published voriconazole PPK models mainly established for adults with
invasive fungal infections15, liver
transplantation16, lung
transplantation17, hematopoietic stem cell
transplantation18 and hematological
malignancies19, while the PPK model of voriconazole in
pediatric patients with hematological malignancies has not been
reported. Therefore, it is necessary to clarify the pharmacokinetic
characteristics of voriconazole in pediatric patients with
hematological malignancies and
optimize the dosing regimen. This study aims to investigate the factors
affecting voriconazole trough concentration (Cmin),
establish a PPK model of voriconazole in children with hematological
malignancies and recommend an appropriate voriconazole dosing regimen
for children with hematological malignancies.