Pharmacokinetic Of Tigecycline In Critically Ill Patients

Part 1:Development and Validation of a UPLC-MS/MS Method for Quantification of Tigecycline in PlasmaObjective: To establish a UPLC-MS/MS method for the determination of tigec ycline in Plasma.Methods: The column was Ultimate AQ C18(3.0×100 mm,3 μm).The mobile phase was water(95% Formic acid,5 mmol/L ammonium acetate)-acetonitrile(gradient elution).The ion transitions were performed under E SI positive MRM model at m/z 586.4→513.3(Tigecycline)、m/z 338.2→296.0(I nternal Standard).Results: Calibration curves of tigecycline showed good linear regression in the range of 50.15~2006 ng/m L(R2=0.9947).The lowest quant ification limit of tigecycline was 50.15 ng/m L.The intra-day and inter-day RS D were below 15%。Plasma sample kept stable at room temperature for 2 h,automatic sample injector for 12 h,-30 °C freezing for 42 d,-80 °C freezing for 72 h,after 3 times of freezing and thawing cycle,-80 °C freezing for 3 months(RSD<15%).Conclusion: The established method is simple,accurate,sensitive and has good reproducible,can be used for the blood concentration determination of tigecycline.Part 2:Study on Pharmacokinetic and Clinical efficacy of tigecycline in Critically Ill PatientsObjective: To investigate the differences in pharmacokinetics of different dosag es of Tigecycline from different manufacturers in critically ill patients and to st udy its clinical efficacy.Providing research basis and medication reference for pharmacokinetic-pharmacological studies.Methods: Enrolled 58 patients who w ere treated with tigecycline in ICU from March 2016 to December 2017.Colle cted blood from 58 patients after administration and measured the blood drug concentration by UPLC-MS/MS method.Winnonlin5.2 software processing to c alculate pharmacokinetic parameters,using SPSS19.0 statistical analysis software for statistical analysis.The basic information of the enrolled patients was reco rded and Patients were grouped according to the different manufacturers(impor ted and domestic)of tigecycline used by the patients and different doses(conv entional and high doses).The pharmacokinetic parameters and clinical efficacy of the hormone were compared and analyzed.Results: At the same dose,the pharmacokinetic parameters of the imported and domestic(Haizhenglixing)grou ps were not statistically different.The Cmax and AUC of the high-dose tigecycl ine group were significantly higher than those of the conventional dose group(P<0.05),but there was no significant difference in t1/2,CLss,and Vd values.T he overall clinical efficacy of the imported group was higher than that of the domestic(Haizhengxing)group,but there was no significant difference.All of the patients used tigecycline have a low clinical effectiveness(62.2% in high-d ose group and 57.1% in low-dose group),A total of 7 patients had drug-relate d adverse reactions and the incidence of adverse reactions was 12.07%.Conclu sion: There was no significant difference in the pharmacokinetics between the i mported and domestic(Haizhenglixing)groups.Increasing the dose of tigecycli ne significantly increased the plasma concentration in the patients but did not a ffect the drug distribution of metabolic processes in the patients.Tigecycline ha s good safety and clinical efficacy is lower than the values reported in many previous studies.The reason may be that the subject’s condition of this study i s more complicated and serious.Clinicians should weigh the advantages and di sadvantages when administering drugs,and conduct monitoring of therapeutic d rugs to perform individualized medications.Part 3:Study on the Influence of CRRT on Pharmacokinetics of Tigecycline in Critically Ill PatientsObjective: To investigate the effect of continuous renal replacement therapy(C RRT)on the pharmacokinetics of tigecycline and to provide a theoretical basis for optimizing the tigecycline dose regimen administration during CRRT treat ment.Methods: 6 patients with CRRT who were treated with tigecycline in IC U from March 2016 to December 2017 were recruited and collected their bloo d before and after the filter at 0 h,0.5 h,3 h,6 h,8 h,and 12 h after the s tart of infusion.Recorded the basic information of patients.The plasma concen tration was measured by UPLC-MS/MS method.The pharmacokinetic parameter s were calculated by Winnonlin5.2 software,and SPSS19.0 statistical analysis s oftware was used for statistical analysis.Results: The blood concentration befo re and after the filter in the 6 patients was(538.17 ± 414.82 VS 463.50 ± 344.30;1619.00 ± 920.12 VS 1268.00 ± 740.19;911.17 ± 639.26 VS 801.83 ± 557.12;760.50 ± 529.08 VS 664.17 ± 485.15;566.00 ± 379.73 VS 533.33 ± 357.24;488.75 ± 361.05 VS 409.33 ± 269.26)ng/m L;The Patient’s Cmin,Cmax,AUC0-12 h,t1/2,CLss,and Vd before and after the filter were 0.48 ± 0.36 VS 0.40 ± 0.27(μg/m L);1.62 ± 0.92 VS 1.27 ± 0.74(μg/m L);9.65 ± 6.31 VS 8.30 ± 5.47(h·μg/m L);11.25 ± 6.53 VS 10.96 ± 5.46(h);13.46 ± 7.92 VS 12.01 ± 7.85(L/h);227.38 ± 295.81 VS 230.99 ± 245.86(L).The AUC value of blood after the filter are 73% times to blood before the filter in patients with high u ltrafiltration rate CRRT treatment,The AUC value of blood after the filter are 95% to 97% times to blood before the filter in patients with low ultrafiltration rate CRRT treatment.Conclusion: Tigecycline may be partially cleared during operation of the entire CRRT extracorporeal device,and the amount of cleara nce increases with the increase in CRRT ultrafiltration rate.Part 4:Study on the Influence of ECMO on Pharmacokinetics of Tigecycline in Critically Ill PatientsObjective: To investigate the effect of extracorporeal membrane oxygenation(E CMO)on the pharmacokinetics of tigecycline and to provide a theoretical basis for optimizing the tigecycline dose regimen administration during ECMO treat ment.Methods: 5 ECMO patients who were treated with tigecycline from Mar ch 2016 to December 2017 were enrolled in the study,and the blood was coll ected at several time points after infusion starting with trough concentrations,p eak concentrations,and peak concentrations after infusion.Record the basic inf ormation of the patients enrolled.The plasma concentration was measured by UPLC-MS/MS method.The pharmacokinetic parameters were calculated by Win nonlin5.2 software,and SPSS19.0 statistical analysis software was used for stati stical analysis.Results: The values of Cmax,AUC0-12 h,t1/2,CLss,and Vd in 5 p atients with high-dose tigecycline were 1.82 ± 0.78 μg/m L、8.60 ± 3.80 h·μg/m L、11.45 ± 1.76 h、14.33 ± 8.27 L/h、228.58 ± 113.22 L.Conclusion: ECM O has no significant effect on the pharmacokinetics of tigecycline in critically ill patients.