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.