Therapeutic drug monitoring and CYP2C19 genotyping guide the application of voriconazole in children

Xiaomin Chen; Yuhua Xiao; Huiping Li; Zhi Huang; Jingyu Gao; Xinyao Zhang; Yirong Li; Bindanda Mvuama Van Timothee; Xiaoqin Feng

doi:10.21037/tp-22-156

Therapeutic drug monitoring and CYP2C19 genotyping guide the application of voriconazole in children

Transl Pediatr. 2022 Aug;11(8):1311-1322. doi: 10.21037/tp-22-156.

Authors

Affiliation

¹ Department of Pediatrics, Nanfang Hospital, Southern Medical University, Guangzhou, China.

^# Contributed equally.

Abstract

Background: This study used therapeutic drug monitoring (TDM) and CYP2C19 gene polymorphism analysis to explore the efficacy and safety of different doses of voriconazole (VCZ) for the clinical treatment of pediatric patients, with the aim of providing guidelines for individualized antifungal therapy in children.

Methods: Our study enrolled 94 children with 253 VCZ concentrations. The genotyping of CYP2C19 was performed by polymerase chain reaction (PCR)-pyrosequencing. VCZ trough concentration (C_trough) was detected by high-performance liquid chromatography-tandem mass spectrometry. SPSS 23.0 was used to analyze the correlations between VCZ concentration, CYP2C19 phenotype, adverse effects (AEs), and drug-drug interactions.

Results: A total of 94 children aged between 1 and 18 years (median age 6 years) were enrolled in the study. In total, 42.6% of patients reached the therapeutic range at initial dosing, while the remaining patients reached the therapeutic range after the adjustment of the dose or dosing interval. CYP2C19 gene polymorphism was performed in 59 patients. Among these patients, 24 (40.7%) had the normal metabolizer (NM) phenotype, 26 (44.1%) had the intermediate metabolizer (IM) phenotype, and 9 (15.3%) had the poor metabolizer (PM) phenotype. No cases of the rapid metabolizer (RM) or ultrarapid metabolizer (UM) phenotypes were found. The initial VCZ C_trough was significantly higher in patients with the PM and IM phenotypes than in those with the NM phenotype. The combination of immunosuppressive drugs (ISDs) did not affect VCZ C_trough. The incidence of AEs was 25.5%, and liver function damage (46.2%) and gastrointestinal reactions (19.2%) were the most common.

Conclusions: Our study showed significant individual differences of VCZ metabolism in children. Combining TDM with CYP2C19 gene polymorphism has important guiding significance for individualized antifungal therapy in pediatric patients.

Keywords: CYP2C19; Voriconazole (VCZ); therapeutic drug monitoring (TDM); therapy.