Voriconazole therapeutic drug monitoring including analysis of CYP2C19 phenotype in immunocompromised pediatric patients with invasive fungal infections.

ABSTRACT

PURPOSE: Therapeutic drug monitoring (TDM) of voriconazole (VCZ) should be mandatory for all pediatric patients with invasive fungal infections (IFIs). The narrow therapeutic index, inter-individual variability in VCZ pharmacokinetics, and genetic polymorphisms cause achieving therapeutic concentration during therapy to be challenging in this population. METHODS: The study included 44 children suffering from IFIs treated with VCZ. Trough concentrations (Ctrough) of VCZ ware determined by the HPLC-FLD method. Identification of the CYP2C19*2 and CYP2C19*17 genetic polymorphisms was performed by PCR-RFLP. The correlation between polymorphisms and VCZ Ctrough was analyzed. Moreover, the effect of factors such as dose, age, sex, route of administration, and drug interactions was investigated. RESULTS: VCZ was administered orally and intravenously at a median maintenance dosage of 14.7 mg/kg/day for a median of 10 days. The VCZ Ctrough was highly variable and ranged from 0.1 to 6.8 mg/L. Only 45% of children reached the therapeutic range. There was no significant association between Ctrough and dosage, age, sex, route of administration, and concomitant medications. The frequencies of variant phenotype normal (NM), intermediate (IM), rapid (RM) and ultrarapid metabolizers (UM) were 41%, 18%, 28%, and 13%, respectively. Ctrough of VCZ were significantly higher in NM and IM groups compared with RM, and UM groups. CONCLUSION: The Ctrough of VCZ is characterized by inter-individual variability and a low rate of patients reaching the therapeutic range. The significant association exists in children between VCZ Ctrough and CYPC19 phenotype. The combination of repeated TDM and genotyping is necessary to ensure effective treatment.