Pharmacogenetic Analysis of Voriconazole Treatment in Children

Abstract

Voriconazole is among the first-line antifungal drugs to treat invasive fungal infections in children and known for its pronounced inter- and intraindividual pharmacokinetic variability. Polymorphisms in genes involved in the metabolism and transport of voriconazole are thought to influence serum concentrations and eventually the therapeutic outcome. To investigate the impact of these genetic variants and other covariates on voriconazole trough concentrations, we performed a retrospective data analysis, where we used medication data from 36 children suffering from invasive fungal infections treated with voriconazole. Data were extracted from clinical information systems with the new infrastructure SwissPKcdw, and linear mixed effects modelling was performed using R. Samples from 23 children were available for DNA extraction, from which 12 selected polymorphism were genotyped by real-time PCR. 192 (49.1%) of 391 trough serum concentrations measured were outside the recommended range. Voriconazole trough concentrations were influenced by polymorphisms within the metabolizing enzymes CYP2C19 and CYP3A4, and within the drug transporters ABCC2 and ABCG2, as well as by the co-medications ciprofloxacin, levetiracetam, and propranolol. In order to prescribe an optimal drug dosage, pre-emptive pharmacogenetic testing and careful consideration of co-medications in addition to therapeutic drug monitoring might improve voriconazole treatment outcome of children with invasive fungal infections.

Clinical application of voriconazole in pediatric patients: a systematic review

“… Chen et al [ 29 ] Retrospective, single-center study 0.5 months to 17 36 2022 Switzerland CYP2C19 and CYP3A4 polymorphisms and drug transporters ABCC2 and ABCG2, combination medication levetiracetam, ciprofloxacin, and propranolol affected VRC C trough . Tilen et al [ 30 ] Prospectively single-center study 2 to 14 68 2022 China VRC C trough of patients with CYP2C19*2 or CYP2C19*3 were significantly higher than that with wild-type carriers. Fan et al [ 31 ] Retrospective, single-center study 2 to 14 131 2023 China CYP2C19 polymorphisms, co-administration of omeprazole, ALB and ALT levels affected VRC C trough .…”

“…Chen et al‘s study [ 29 ] found that 15.3% of patients were CYP2C19 poor metabolizers (PMs), a proportion higher than that reported in European and American populations. Allegra et al [ 23 ] and Tilen et al [ 30 ] reported that apart from CYP2C19 genotypes, genetic polymorphisms in CYP3A4, SLCO1B3, as well as ABCC2 and ABCG2 also significantly influenced VRC C trough .…”

Pharmacogenetic and clinical predictors of voriconazole concentration in hematopoietic stem cell transplant recipients receiving CYP2C19-guided dosing

“…In a larger study of 233 pediatric patients receiving voriconazole treatment, SNPs in SLCO1B3, ABCG2, and ABCB1 were signi cantly associated with trough concentrations (19). A study of 36 pediatric patients receiving voriconazole treatment demonstrated that CYP2C19, CYP3A4, ABCC2, and ABCG2 were associated with voriconazole concentrations (20). However, the minor allele frequency for CYP3A4 was 5%, and the study sample size was small.…”

Enhancing voriconazole therapy in liver dysfunction: exploring administration schemes and predictive factors for trough concentration and efficacy

“…Overall, the VRZ daily dose was positively correlated with its trough concentration significantly, which demonstrates that the necessity of reducing the VRZ dose in patients with liver dysfunction. Besides, some other factors that contribute to unpredictability of VRZ trough concentrations have been reported in published literature, such as inflammation ( van Wanrooy et al, 2014 ; Encalada Ventura et al, 2016 ), polymorphism within drug transporters ( Tilen et al, 2022 ), and the use of extracorporeal membrane oxygenation ( Ye et al, 2022 ). In the analysis of relationship between CYP2C19 and initial VRZ trough concentration, our results were similar to previously studies ( Kim et al, 2019 ; Zhang et al, 2021 ).…”