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

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 drugdrug 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.

Optimization of Voriconazole Dosing Regimens Against Aspergillus Species and Candida Species in Pediatric Patients After Hematopoietic Cell Transplantation: A Theoretical Study Based on Pharmacokinetic/Pharmacodynamic Analysis

“…Furthermore, risk-benefit analysis should be performed in combination with the patient's actual situation. 41,42 In addition, in this study, we used fAUC/MIC > 25 as the PK/PD index; it should be noted, however, that when AUC/MIC is used as a predictor, its target value should also be adjusted. 43 The current study has several limitations that need to be considered.…”

“…Therefore, dose adjustments should be combined with TDM to reduce the risk of adverse reactions. Furthermore, risk‐benefit analysis should be performed in combination with the patient's actual situation 41,42 . In addition, in this study, we used f AUC/MIC > 25 as the PK/PD index; it should be noted, however, that when AUC/MIC is used as a predictor, its target value should also be adjusted 43 …”

Voriconazole plasma concentrations and dosing in paediatric patients below 24 months of age

“…The disposition of VCZ involves age‐dependent, saturable oxidative hepatic metabolization through CYP2C19, CYP3A4 and, to a lesser extent, CYP2C9, resulting in non‐linear PKs and unpredictable dose–exposure relationships 8,24 . The compounds disposition in children is further influenced by highly variable genetic polymorphisms in CYP2C19, relevant drug–drug interactions particularly via CYP3A4 and CYP2C19, inflammation and variable oral bioavailability through an intestinal first‐pass metabolism and food effects 8,15,24,33–38 . Indeed, in larger population PK analyses 31,32,39 and in a physiologically based pharmacokinetic model 40 including children <24 months of age, the CYP2C19 phenotype and age were consistently found as the significant covariates.…”

Establishment of a mathematical prediction model for voriconazole stable maintenance dose: a prospective study

“…in Chinese populations (50.0%, 6.3%, and 2.1%) ( Zuo et al., 2012 ; Botton et al., 2021 ). It is well known that genetic polymorphism of CYP2C19 can cause phenotypic variability ( Chen et al., 2022 ), contributing to the high variability of VCZ exposure, affecting drug efficacy, and leading to ADRs.…”