The Establish Of Vancomycin Population Pharmacokinetic Model And Clinical Application Research

Objective:(1)To build a population pharmacokinetic(PPK)model for Chinese adult patients and develop initial dosage regimens for patients with different degrees of renal function to achieve target steady-state trough concentrations in the range of 10～15 and 15～20 mg/L.(2)To analyze the clinical application of PPK model and to investigate the clinical efficiency of serum cystatin C(Cys C)as a maker of renal function to predict serum trough concentrations of vancomycin.(3)To analyze the renal toxicity of vancomycin in Chinese adult patients.Methods:(1)Data involved the cases of hospitalized patients receiving vancomycin therapy in The First Affiliated Hospital of Guangxi Medical University were collected,such as age,gender,height,weight,hepatorenal function,co-administration,basic disease,microbiologic data,vancomycin dosing regimen,trough concentrations and length of hospitalization prior to vancomycin.(2)A one-compartment model was chosen to describe the vancomycin concentration-time profile,NONMEM was used to build the PPK model.Internal evaluation by bootstrap and visual predictive check(VPC)was performed to evaluate the robustness and prediction of the final model.Monte Carlo simulations were conducted to develop initial dosage regimens to achieve target trough concentrations.(3)PPK model combined with Bayesian forecasting method was used to implement individualized dosage regimen.On the basis of vancomycin PPK model which has been established,predicted vancomycin trough concentrations(Cpre)were calculated based on Scr or Cys C concentrations associating with Bayesian forecasting method through NONMEM software.Finally,comparative analyzed the correlations and distinctions between Cpre and Cmea.(4)According to the average blood trough concentration the patients were divided into four groups:1)trough<10mg/L,2)trough 10～14.9mg/L,3)trough 15～20mg/L,4)trough>20mg/L,respectively.Comparative analysis of renal toxicity with each group,and potential risk factors associated with vancomyc.in nephrotoxicity were evaluated using multivariate analysis.Results:(1)Creatinine clearance(CLcr)was the key covariate influencing drug clearance.The estimated drug clearance for patients with normal renal function(CLcr≥80 mL/min)was 4.90(L/h),and 0.0654×CLcr(L/h)if CLcr was<80 mL/min.The apparent volume of the central compartment was 47.76 L and no co variate was found to affect it.The results of bootstrap analysis were in agreement with the original parameters of the final model,and VPC of the final model demonstrated good predictability.Vancomycin initial dosage regimens were developed based on the simulations of the PPK model.(2)The application of PPK model might be benefit to instruct clinical medication.There were both correlation between Cpre and Cmea in relation to Scr(r=0.678,p<0.001)or Cys C(r=0.727,p<0.001).Besides,the errors of ME,MAE and RMSE for Scr was-5.79,6.86,9.86 mg/L,respectively,whereas the errors for Cys C was-0.82,5.42,7.74 mg/L,respectively.(3)The incidence of renal toxicity of trough<10mg/L,trough 10-14.9mg/L,trough 15-20mg/L,trough>20mg/L was 7.94%,11.36%,0%,30.00%,respectively.Trough>20mg/L the incidence of renal toxicity was significantly higher than trough 15-20mg/L(P=0.004).The result of multivariate analysis indicated vancomycin trough concentration(Odds ratio=1.19,P<0.001),duration of vancomycin therapy(Odds ratio=1.06,P=0.02)and MODS(Odds ratio=5.32,P=0.02)as significant predictors of nephrotoxicity.Conclusions:(1)CLcr has a significant effect on drug clearance.Initial dosage regimens for vancomycin are proposed to provide some help to individual therapy for Chinese adult patients with different renal functions.(2)PPK model combined with Bayesian forecasting method can be use to implement individualized dosage regimen.Cystatin C is a good marker of renal function available for predicting serum vancomycin concentrations.(3)Trough>20mg/L has a high incidence of renal toxicity,a higher vancomycin troug concentration,prolonged vancomycin therapy and MODS may be the risk factors for nephrotoxicity.