| Objective:Based on the analysis of TDM(Treatment Drug Monitor)and CYP2C19 gene polymorphism analysis,this paper was to explore the characteristics of voriconazole trough concentrations and its impact on the effectiveness and safety of clinical treatment;meanwhile,the effects of combined use of immunosuppressant on voriconazole trough concentrations in children were analyzed to provide guideline for individualize antifungal therapy in children.Methods:Retrospective analysis was performed on total 94 children considered invasive fungal infections in pediatric department Nanfang Hospital affiliated to Southern Medical University from June 1st,2015 to April 30th,2020.Monitor the voriconazole trough concentrations during hospitalization,adjust the dose and interval of administration according to the trough concentrations and maintain the range of 2.00-6.00mg/L.Some of them improved the detection of CYP2C19 gene polymorphism.The clinical characteristics of the patients,the drug dose and dosage adjustment of Voriconazole at the same period,the route and interval of drug administration of Voriconazole,whether combined use of immunosuppressant,antifebrile time under the guidance of voriconazole concentration monitoring,and the CT imaging data of the lungs were collected.SPSS23.0 was used to analyze the characteristics affecting the voriconazole trough concentrations in children,the correlation between CYP2C19 gene polymorphism and the voriconazole trough concentrations,and the clinical efficacy and safety under the guidance of TDM.Results:Total 94 children were enrolled in the study,including 57 boys(60.7%)and 37 girls(39.4%),with a median age of 6 years old.There were 51 cases suspected diagnosed with invasive fungal disease,38 cases clinically diagnosed with invasive fungal disease and 5 patients were diagnosed with invasive fungal disease.There were 59 patients that detected CYP2C19 gene polymorphism,in which 24 cases(40.7%)were normal metabolizer phenotypes,26 cases(44.1%)were intermediate metabolizers and 9 cases(15.3%)were slow metabolizers,no case of rapid metabolizer and ultrarapid metabolizer phenotypes was found.The initial voriconazole trough concentrations was 1.12±0.92mg/L for the normal metabolizer phenotypes,3.41±3.27mg/L for the intermediate metabolizers and 6.30±4.18mg/L for the slow metabolizers,respectively.There was significantly different in the initial voriconazole trough concentrations among various metabolizer phenotypes(P=0.000,P=0.005,P=0.009).The initial treatment started with voriconazole 6-8mg/kg,only 42.6%of patients reached therapeutic concentration,with initial voriconazole trough concentrations ranging from 0.16 to 15.37mg/L.However,31 patients adjusted their trough concentration by adjusting voriconazole dose,13(41.9%)were in the subtherapeutic state,and 18(58.1%)were in the high therapeutic state.The voriconazole concentration was 3.96±4.09mg/L before dose adjustment and 2.07±1.04mg/L after dose adjustment,with significantly different(P=0.015).17 patients were adjusted the dosing intervals,the Voriconazole concentration was 0.96±0.88mg/L at the q12h,and 2.18±1.37mg/L at the q8h.There was a difference in the voriconazole trough concentrations(P=0.004).The 14 patients were treated with both voriconazole and immunosuppressant,and the voriconazole trough concentrations was 2.98±3.19mg/L when used alone and 1.88±1.31mg/L when combined with immunosuppressant.However,no significant difference was observed before and after the use of immunosuppressant(P=0.252).Voriconazole trough concentrations before and after allogeneic hematopoietic stem cell transplantation were 3.28±2.84mg/L and 1.73±1.08mg/L,respectively,with no significant difference in trough concentration before and after transplantation(P=0.186).Multivariate analysis showed that the initial trough concentration of voriconazole increased trend with age.The mean voriconazole concentration(6.30mg/L)of patients with CYP2C19 slow metabolism was significantly higher than that of patients with normal metabolism(1.12mg/L)and intermediate metabolism(3.41 mg/L).The median of antifebrile time was 3 days,the target therapeutic response rate was 80.0%,the clinical imaging improvement rate was 68.4%,and the incidence of adverse reactions was 25.5%,with no significant difference between boys and girls.Liver function damage(46.2%)and gastrointestinal reactions(19.2%)were the most common side effects,and the incidence of adverse reactions was high in children with slow metabolism(1/9).Conclusion:The proportion of the initial voriconazole trough concentrations in children reaching the required range of therapeutic concentration was only 42.6%,and it was easier to reach the treatment concentration by adjusting the dosing interval than by adjusting the dosing.The use of immunosuppressive agents had no significant effect on the voriconazole concentration.CYP2C19 gene polymorphism has a significant influence on voriconazole trough concentrations in children and has a certain predictive effect on TDM.There are significant individual differences of voriconazole metabolism in children.Combining with TDM and CYP2C19 gene polymorphism has important guiding significance for individualize antifungal therapy in children. |
