| Objective:Voriconazole（VRZ）is the first-line antifungal choice in the treatment of invasive fungal infections,and it displays highly variable pharmacokinetics.Single nucleotide polymorphisms（SNPs）in drug-metabolizing and transporter genes may affect VRZ pharmacokinetics.VRZ trough concentration is affected by many factors.This study aimed to identify the pharmacogenetic factors and clinical factors affecting VRZ steady-state trough concentration（Cssmin）to provide evidence for optimizing VRZ therapeutic drug monitoring（TDM）and individualized administration.Method:Patients from all departments who underwent at least once VRZ TDM from December 2015 to December 2021 were included,and the corresponding demographic and clinical information were collected.Concentration were analyzed,and a multiple linear regression model was constructed.A total of 33 SNPs of 15 candidate genes were selected and genotyped by"Next-generation"sequencing technology.Non-parametric test,Chi-square test,spearman correlation analysis,multiple linear regression analysis,logistic regression analysis were used to explore the influence of genetic factors,renal function and other non-genetic factors on VRZ Cssmin.And identify the risk factors for subtherapeutic and supratherapeutic Cssmin of VRZ.Results:A total of 1390 cases of VRZ Cssmin in 394 patients were included in this study.VRZ Cssmin in hematopoietic stem cell transplantation department was significantly lower than that in other departments（P<0.001）.The VRZ Cssmin of ABCB11 rs2287622 mutant genotype was significantly lower（P=0.003;P=0.031）.The VRZ Cssmin of CYP2C19 poor metabolizers is higher than that of rapid,normal and intermediate metabolizers,and the risk of subtherapeutic Cssmin also is lower.Intravenous administration（P=0.030）,Serum creatine（P=0.007）,total bile acid（P=0.012）,NR1I2 rs2461817（P=0.044）,SLCO1B1rs4149056（P=0.019）,POR rs2228104（P=0.034）and CYP2C19metabolizers（P=0.031）were independent factors affecting VRZ Cssmin.The median VRZ Cssmin of NFKB1 rs230521 CG/GG genotype carriers was significantly lower than that of CC genotype carriers（CG vs.CC,OR=0.223,P=0.040;GG vs.CC,OR=0.166,P=0.044）.Patients with low albumin levels,low creatinine clearance,intravenous administration,and PPIs were at higher risk of having VRZ Cssmin beyond the treatment window(0.5-5.0μg·m L-1).（2）In 281 patients（895 cases）,it showed that VRZ Cssmin and creatinine were positively correlated（r=0.155,P<0.001）,and creatinine clearance showed a trend of negative correlation（r=-0.167,P<0.001）.Among the genes,only the most influential CYP2C19 was included in multiple linear regression analysis,adjusting for other confounding factors,and gender（P=0.026）,albumin level（P<0.001）,urea（P=0.022）,procalcitonin（P=0.005）,renal function（P=0.002）,CYP2C19 metabolic type（P=0.011）were the independent factors affecting VRZ concentration.Conclusion:The high variability of VRZ Cssmin was related to liver and kidney function,procalcitonin,route of administration,drug combination and gene polymorphism of CYPs,NFKB1,POR and SLCO1B1.There are differences in VRZ Cssmin in different clinical diseases.Augmented renal clearance patients had lower VRZ Cssmin than patients with normal and hyporenal renal function. |
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