Population Pharmacokinetics And Pharmacodynamics Of Voriconazole In Patients With Invasive Fungal Diseases

Objectives1.To establish an UPLC-MS/MS method for determination of voriconazole and its metabolite N-Oxide VOR plasma concentration.2.To explore the effect of CYP2C19 gene polymorphism on voriconazole population pharmacokinetic parameters.3.To establish a pharmacokinetic and pharmacodynamic model of voriconazole in patients with invasive fungal disease,evaluating the advantages and disadvantages of different dosing regimens and providing a reference for clinical individualized drug delivery.Methods1.The plasma concentration of voriconazole and N-Oxide voriconazole was determined by UPLC-MS/MS.2.Gene sequencing was used to detect CYP2C19 gene polymorphism.3.The non-linear mixed effect model?NONMEM?method was used to investigate the effects of physiological,liver and kidney function,combined drug use and CYP2C19 gene polymorphism on the population pharmacokinetic parameters of voriconazole in patients with invasive fungal disease.The goodness of fit of the PPK model was investigated using the graph method.The bootstrap method was used to verify the validity and stability of the PPK model.The normalized predictive distribution Error?NPDE?was used to evaluate and the prediction performance of the model.Bayesian feedback method was used to externally validate the measured values of clinical voriconazole blood concentration.4.Combine the PPK model with the fungal biomarkers to establish a voriconazole PD model.The bootstrap method was used to verify the validity and stability of the PD model.The normalized predictive distribution Error?NPDE?was used to evaluate and the prediction performance of the model.5.Voriconazole PPK/PD models were recommended for voriconazole individualized drug delivery regimens in several patients.Results1.The concentrations of voriconazole and N-Oxide voriconazole in 100 patients was determined by UPLC-MS/MS method.The range of voriconazole plasma concentrations was 0.15 to 27.3?g�mL^-1,and the range of N-Oxide voriconazole plasma concentrations was 0.07 to 4.6?g�mL^-1.2.The CYP2C19 genotype distribution frequency in 100 patients with invasive fungal disease were:extensive metabolizer:?41 cases,41%?;intermediate metabolizer:?40 cases,40%?;poor metabolizer:?19 cases,19%?.3.The formulas of final voriconazole population pharmacokinetic model are:CL=[3.67�?1.13/N-OVOR?0.24�0.66PM]�e044 V=38.3Ci,ob=Ci,p+e???i,obs4.Based on the voriconazole PPK model,the fungal biomarker GM,the PD model's formulas are:dA1/dt=CL�A1/V EGM=S0+Emax�A1/V/EC50+A1/V S0=1.28 Emax=-1.27 EC50=1.60�e0.54 Ci,pd=Ci,pdp+???i,pdConclusions1.The UPLC-MS/MS method to determine voriconazole and N-Oxide voriconazole concentration was convenient,fast with good accuracy,and it can be used in clinical routine detection.2.The voriconazole metabolites N-Oxide VOR and CYP2C19 PM genotypes were covariates that significantly affected the voriconazole clearance in the PPK model.3.The voriconazole PPK/PD models established in this study were effective and stable,which can provide a scientific basis for clinical individualized drug delivery programs.