Study On The Pharmacokinetics Of Voriconazole In Critically Ill Patients With ECMO

ObjectiveVoriconazole is the first-line drugs for antifungal,whose pharmacokinetic characteristics is nonlinear,existting differences within the individual and individuals.The critically ill patients often need the adjuvant therapy in vitro,therefore,voriconazole pharmacokinetic changes in whom is more complex,bringing a big challenges to critically ill patients treated with voriconazole.For momitoring voriconazola plasma concentration in clinical,to build a simple,rapid and accurate method for the determination of voriconazole concentration in human plasma.To analyze the factors affecting the trough concentration and optimize the clinical application of voriconazole by monitoring voriconazole serum trough concentration in critically ill patients.An in vitro experiment with continuous administration was conducted to investigate the effect of ECMO on voriconazole.To explore the pharmacokinetics change characteristics of voriconazole in critically ill patients with ECMO,and to provide reference for the formulation and adjustment of voriconazole clinical therapy regimen.MethodsMethodology:The method was established for the determination of voriconazole plasma drug concentration,and then the specificity,accuracy,precision and stability were verified.Influence factors analysis:The critically ill patients who received intravenous voriconzole and had trough concentration monitored were retrospectively selected from January 2018 to January 2020 in an University Affilicated hospital,collecting their information including age,sex,the score of SOFA score and APACHE Ⅱ score,dose,voriconazole trough concentration and on the same day of laboratory testing,the medication combinated with voriconazole and adjuvant therapy which were analyzed with the aid of statistical software.ECMO Vitro experiment:The ECMO loop was full of human fresh whole blood and maintain within the scope of the normal physiological conditions,voriconazole was added into the ECMO loop every 12 h,respectively in dosing,pre-membrane oxygenator and post-membrane oxygenator to take blood samples and determination of the concentration,calculated at different time points of blood in the blood recovery.Pharmacokinetics of voriconazole with ECMO:To select the critically ill patients with ECMO in an University Affilicated hospital between January 2020 and January 2021 in intensive care unit(ICU)according to inclusion and exclusion criteria and then blood samples were taken before injection and at 0.5h,1h,1.5h,2h,3h,4h,6h,8h,10h and 12h after injection,the trough concentration were collected every doseage interval as well.The sample were determined by high-performance liquid chromatography(HPLC)method,and the pharmacokinetics parameters were calculated with the help of the WinNonlin software program.ResultsMethodology:The method determining voriconazole plasma concentration fitted to the requirements of biological samplesin in vivo,and had a good specificity.When the concentration was 0.16-10.2mg/L,the linearity was good,y=0.42x-2.76×10-2(r=0.998),the lower limit of quantification was low(0.08mg/L),which could cover the therapeutic range of voriconazole effective trough concentration(0.50-5.00mg/L),and the extraction recovery was enough high(>90%).The precision,accuracy,extraction recovery and stability were all in line with the requirements.Influence factors analysis:267 times of voriconazole plasma trough concentration in 116 critically ill patients were enrolled,and it showed that the mean state trough concentration was 3.18±2.19mg/L and distributed from 0.34 to 14.77mg/L.76.00%(203/267)of trough concentration were within the effective therapeutic concentration range(0.50-5.00mg/L).The univariate and multivariate analysis found that the factors including age,sex,daily dose of kilogram,ALT,AST,total protein and albumin had significant effects on voriconazole trough concentration,among them,the daily dose of kilogram,AST and ALB were the independent risk factors affecting voriconazole trough concentration.When the daily dose of kilogram was in the range of(2.00-14.29mg/(kg·d))and ALB was in the range of(15.6052.0g/L),the regression equation could be established as follows:Cmin=1.22+0.31X1+0.361nX2-0.52(X3-32.89)/5.16(X1 was daily dose of kilogram,X2 was AST and X3 was ALB).ECMO Vitro experiment:The cardiopulmonary bypass was maintained under physiological conditions for 96h.Voriconazole was added to the circuit for 8 times consecutively.A total of 179 blood samples were collected.After the first administration,the recoveries of voriconazole in the ECMO circuit at 12h measured at M,H and J were 52.50%,42.41%and 60.36%,respectively.At the 7th administration,the recoveries of M,H and J at 3h,6h and 12h were all more than 100%.In the course of multiple administration,there was no significant difference between the recovery of voriconazole pre-oxygenator membrane and post-oxygenator membrane at 12h.Pharmacokinetics of voriconazole with ECMO:A total of 4 criticially ill patients with ECMO were collected,including 2 females and 2 males,one patient received V-A treatment mode and three patients received V-V treatment mode,and one male patient received CRRT during ECMO treatment.The mean peak concentration of the four patients was 7.37 ±2.75mg/L,and the distribution volume of the four patients was:165.74L,147.00L,170.82L and 454.60L;the clearance rates were 6.22L/h,8.14L/h,3.95L/h and 2.19L/h,respectively.Compared with the previous research results of the research group,the distribution volume increased,there was no significant difference in clearance.Conclusion①The method of voriconazole plasma concentration detection had good specificity,high accuracy and simple operation,which can be applied to clinical monitoring of voriconazole.② The factors including age,sex,the daily dose of kilogram,ALT,AST,total protein,and albumin affected voriconazole trough concentration;the daily dose of kilogram,AST,ALB were independent risk factors affecting voriconazole trough concentration.The trough concentration of voriconazole varied greatly,so it was recommended to monitor the voriconazole concentration in critically ill patients.③Voriconazole was easily adsorbable in the ECMO loop,and the recovery rate was 51.76%after 12 hours.Oxygenator membrane may have effect on voriconazole.Voriconazole had adsorption saturation in the ECMO loop,which could reach the adsorption saturation after the seventh consecutive administration,and the adsorption saturation maintained a dynamic equilibrium.④ECMO may increase the distribution of volume of voriconazole;when combined with ECMO and CRRT,CRRT may not affect voriconazole distribution volume.Liver function affects voriconazole clearance rate and the clearance rate decreased when voriconazole metabolism was saturated.