| ObjectiveInvasive fungal infection is one of the most serious opportunistic infections in childhood.Although voriconazole has been recommended as the first-line drug for the treatment or prevention of fungal infection by many guidelines,it is necessary to explore the safety and effectiveness of voriconazole in children due to their unique physiological characteristics and drug metabolism.The aim of this study was to reveal the effects of CYP450 enzyme related genes(CYP2C19,CYP2C9,CYP3A4,CYP3A5)and ABCB1 gene mutations,as well as non-genetic factors,on the blood concentration of voriconazole in children,so as to provide reference for exploring individualized treatment of voriconazole in children with IFI.Methods1.Case data: From January 2019 to December 2019,a total of 50 children with invasive fungal infection were hospitalized in a special Children’s Hospital in Shanghai and received voriconazole intravenous therapy(29 males,21 females,< 2 years old 19 cases and ≥ 2 years old 31 cases)According to the diagnostic criteria of IFI in children,5 cases were confirmed and 45 cases were clinically diagnosed.2.Detection of plasma drug concentration: Blood samples were collected 0.5 hours before the 4th day after administration,and the plasma trough concentration of voriconazole was monitored by HPLC.3.Clinical data collection: Collect the data of age,gender,weight,body surface area,basic diseases,combined medication,clinical efficacy,adverse reactions,laboratory tests and voriconazole dosage,then establish the corresponding data base.4.Related gene detection: CYP2C19,CYP2C9,CYP3A4,CYP3A5,ABCB1 gene loci were detected by time of flight mass spectrometry,and single nucleotide polymorphisms(SNPs)were genotyped according to the detection results.5.Statistical analysis: Comparative analysis of related gene SNPs typing and nongenetic factors on plasma trough concentration of voriconazole,as well as the efficacy and adverse reactions of voriconazole in children.Results1.Efficacy and adverse reactions: After voriconazole treatment,the total effective rate was 84%(42/50).The incidence of adverse reactions was 20%(10/50 cases),including 9cases of liver function injury and 1 case of allergic rash,which were controlled and did not affect the treatment.2.Clinical significance of plasma drug trough concentration: The range of voriconazole trough concentration was 0.16-7.62 μg/ml(2.563±1.878 μg/ml).The results showed that the effective rate of 1.0-5.0 μg/ml group(93.3%)was significantly higher than that of < 1.0μg/ml group(61.5%)and > 5.0 μg/ml group(85.7%),P=0.033;the incidence of adverse reactions was significantly reduced(P=0.018),indicating that the target trough concentration was 1.0-5.0 μg/ml.3.Influencing factors of age and weight: There was no significant difference in the total effective rate between < 2 years old group and ≥ 2 years old group(84.2% vs 87.1%,P =0.775),but the incidence of adverse reactions in < 2 years old group(5.3%)was lower than that in ≥ 2 years old group(29.0%),P = 0.041.In addition,there was a positive correlation between body weight and trough concentration(r=0.392,P=0.029).Under the condition of no significantly different mean of voriconazole steady-state trough concentration,the average dose of < 2-year-old group was significantly higher than that of ≥ 2-year-old group(F=6.952,P=0.011).4.CYP2C19 gene polymorphism was significantly correlated with voriconazole plasma concentration:(1)Gene locus: The plasma drug concentration of CYP2C19*2mutation homozygote was significantly higher than that of mutant heterozygote and wild homozygote(F=8.208,P=0.001);(2)Enzyme metabolic activity: Different mutation types of CYP2C19 gene site produced three kinds of metabolic activities: extensive metabolism in 16 cases,intermediate metabolism in 27 cases and poor metabolism in 7 cases.There was significant difference in plasma concentration among the three groups(F=15.359,P<0.001),and the drug concentration in extensive metabolism group was significantly lower than that in intermediate metabolism group and poor metabolism group.5.Correlation between ABCB1 gene polymorphisms and voriconazole plasma concentration: The drug concentration of ABCB1(rs1045642)partial mutation patients was(0.548 ± 0.312)μg/ml,which was significantly higher than that of wild homozygotes(0.309± 0.284)μg/ml(F=4.139,P=0.046).Conclusions1.Voriconazole is effective in the treatment of children with invasive fungal infection,and the adverse reactions are mild,especially in children under 2 years old.It is worthy of clinical application.2.1.0-5.0mg/L can be recommended as the referential target trough concentration of voriconazole in the treatment of IFI in children,which can ensure significant curative effect and improve clinical safety.3.Body weight has a certain effect on voriconazole concentration.Under the monitoring of drug concentration,the lighter the weight of infants,there may be a large range for drug dose adjustment.4.Mutation of related genes is an important influencing factor of voriconazole plasma concentration.CYP2C19 genotype is significantly related to drug metabolism rate,and ABCB1 gene mutation may lead to the increase of voriconazole trough concentration.5.The results of this study suggest that comprehensive studies on the blood drug concentration of voriconazole in children and its influencing factors,related gene mutations and metabolic rate,as well as efficacy and safety,will be helpful for clinical adjustment of effective drug dose and realization of more scientific individualized treatment. |
PDF Full Text Request