Population Pharmacokinetics And Pharmacodynamics Of Fluoroquinolones In Patients With Infectious Disease

OBJECTIVE:To establish the population pharmacokinetic model and explorer PK/PD relationship of levofloxacin and moxifloxacin in patients with infectious disease,so as to provide basis for the optimal treatment regimen.METHODS:1.①The determination of levofloxacin sample was performed on Kromasil C18(150mm×4.6mm.5μm)column with a fixed sample injection volume of 10μL.The mobile phase was 0.05mol·L-1 potassium dihvdrogen phosphate solution(pH adjusted to 3.1 by phosphoric acid)-acetonitrile(85:15,V:V)at a flow rate of 1.0 mL·min-1.The UV detective wavelength was set at 294nm;the column temperature was the same as the room temperature and metronidazole was chosen as the internal standard.②The determination of moxifloxacin sample was performed on Kromasil C18(250mm×4.6mm.5μm column with a fixed sample injection volume of 20μL.The mobile phase was 1%triethviamine(pH adjusted to 4.8 by phosphoric acid)-acetonitrile(80:20,V:V)at a flow rate of 1.0 mL·min-1.The UV detective wavelength was set at 296nm the column temperature was the same as the room temperature and ciprofloxacin was chosen as the internal standard.2.PPK/PD model of levofloxacin:A population pharmacokinetic model of levofloxacin was constructed from data of adult patients with infectious disease.A total of 27 patients treated with intravenous levofloxacin 500mg every day.Totally 49 plasma samples of levofloxacin were collected either immediately after intravenous dripping or before application on the 3rd.4th or 5th day.Nonliner mixed effect model was employed using a one-compartment model of levofloxacin.Bootstrap was applied to validate the model.Evaluating the anti-infective effects.and study the PK/PD relationship by using logistic regression.3.PPK/PD model of moxifloxacin:A population pharmacokinetic model of moxifloxacin was constructed from data of adult patients with infectious disease.A total of 37 patients treated with intravenous moxifloxacin 400mg every day.Totally 67 plasma samples of moxifloxacin were collected.Other steps were the same as levofloxacin.RESULTS:1.①Levofloxacin:the retention time of metronidazole and levofloxacin were 4.2min and 8.3min respectively.The lowest detectable concentration was O.Sμg.mL-1.The calibration curve was Y=2.824X+0.065(r2=0.999)and it was linear within the concentration range of 0.05-10μg·mL-1.The absolutely recoveries of moxifloxacin at three concentrations(0.1,0.5,2.0μg·mL-1)were 96.59%.93.87%.85.58%,respectively;the method recoveries were 101.00%.97.35%,103.35%.respectively;with inter-day RSD at 8.73%,2.35%.0.20%and intra-day RSD at 7.53%,2.73%.0.34%.respectively.②Moxifloxacin:The retention time of moxifloxacin and ciprofloxacin were about 15 min and 5.5min respectively’.The calibration curve was Y=3.0506X-0.0235(r2=0.9998)and it was linear within the concentration range of 0.025-5.0μg·mL-1.The absolutely recoveries of moxifloxacin at three concentrations(0.05、0.5、2.5μg·mL-1)were 69.88%.78.86%.78.51%.respectivel)y;the method recoveries were 98.50%,96.61%,101.79%,respectively;with inter-day RSD at 4.120%,3.12%,1.85%and intra-day RSD at 4.70%.1.16%,3.38%,respectively.And the repeatability RSD was 1.67%.2.PPK model of levofloxacin was established.Validating the fixed effect.AGE.AST were identified as intrinsic factors which sigynificantly affected clearance(P<0.05)and AGE.AST significantly affected the apparent volume of distribution(P<0.05).The final model was CL=8.8-2.96*(AGE/50),V=62.8-0.33*AGE+O.302*AST.Internal validation for 300 times in the bootstrap.273 runs successfully.The success rate was 91.0%.The difference between parameter value and final model parameters was not significant.The PK/PD relationship was P(y=EFF)=Exp(-4.607+0.87AUC/MIC)/(1+Exp(-4.607+0.87AUC/MIC)).3.PPK model of levofloxacin was established.Validating fixed effect.WT.AGE were identified as intrinsic factors which significantly affected clearance(P<0.05)and WT significantly affected the apparent volume of distribution(P<0.05).The final model was CL=16.8-4.55*(AGE/50),V=90.2+0.781*(WT-70).Internal validation for 400 times in the bootstrap.382 runs successfully.The success rate was 95.5%.The difference between parameter value and final model parameters was not significant.The PK/PD relationship was P(y=EFF)=Exp(4.085+0.051AUC/MIC-0.097AGE)/(1+Exp(4.085+0.051AUC/MIC-0.097AGE)).CONCLUSION:The HPLC method is simple,rapid,accurate,and had high sensitivity,good specificity and reproducibility,which can be used to determine the drug concentration in plasma for clinical and pharmacokinetic research.Good correlation was showed between forecast values and measured values in both levofloxacin and moxifloxacin PPK models.There were no trends of distribution between weighted residuals and sample collection time,prediction of concentration.The models were stable and reliable that can be used to simulate individual pharmacokinetic parameters.The PK/PD relationship can provide basis for individual medication.