A Population Pharmacokinetic Model Of Vancomycin In Adult Patients Based On Cystatin C And It’s Clinical Application

Objectives:（1）The aim of this study was to develop a population pharmacokinetics（PPK）model of vancomycin in Chinese adult patients based on the renal function marker of Cystatin C（CysC）;（2）The optimal dosing regimens for targeted steady-state trough concentrations(C_ss)of 10～15 mg/L and 15～20 mg/L for different levels of renal function were formulated;（3）The effectiveness and practicality of the established PPK model for clinical application in guiding the individualized dosage of vancomycin were evaluated.Methods:（1）Adult patients aged≥18 years old and received intravenous vancomycin≥72 hours were prospectively included.At least one C_ssand one steady-state plasma peak concentration were collected for each patient.The demographics,renal function-related indicators,major diagnosis,vancomycin dosing regimens,administration time,blood collection time,and vancomycin concentration values of the patients were recorded.（2）A vancomycin PPK model was built through nonlinear mixed effects modeling（NONMEN）approach with glomerular filtration rate（GFR）as a covariate of renal function,which is estimated by CysC.The stability and predictive performance of the final model were examined by internal evaluations and external evaluation.Internal evaluations included Goodness of fit plots（GOFs）,Bootstrap method and visual predictive check（VPC）.A new group of patients and vancomycin plasma concentration data were used for external evaluation.（3）Monte Carlo simulation method was used to simulate different dosing regimens for C_ssreached 10～15 mg/L and 15～20 mg/L at different renal function levels,and the probability of target acquisition（PTA）was calculated.Then the optimal dosing regimens were recommended for corresponding targeted concentrations with different renal function levels.（4）The combination of PPK modle and Bayesian feedback method was used to guide the reasonable individualized initial dosage regimen and adjusted dosage regimen for clinical application.The effectiveness and practicality of the the PPK model was evaluated by calculating the predicted error between detective value of C_ssand individual prediction value at corresponding time piont.Results:（1）The vancomycin PPK model analysis included 200 patients with 514 plasma concentration samples and their relevant pathophysiological information,and the GFR estimated by CysC was the renal function covariate.The pharmacokinetic parameters were estimated by the first-order conditional estimation with interaction（FOCEI）method.The final model was a one-compartment model which was formulated as:CL（L/h）=[5.07×（GFR/105.5）^0.524×（AGE/48.5）^{（（-0.309））}×（WT/60）^0.491]×e^0.0432;V（L）=46.3×e^0.0329.GOFs showed that the predictive values of the final model correlated well with the measured values,and most of the residuals were uniformly distributed symmetrically on the X-axis within±2.Bootstrap found that the robustness rate of the model was 93.2%,and the median value of the estimated pharmacokinetic parameters were close to that of the final model.VPC showed that the 90%prediction interval contained most of the measured concentrations.External evaluation showed that the mean prediction error（MPE）,mean absolute error（MAE）,and root mean square error（RMSE）were-0.97,4.38,and 6.02respectively.Both internal and external evaluations revealed a good stability and predictive performance of the final model.（2）The recommended optimal dosing regimens for different renal function levels were simulated by the PPK model,and the average PTA for C_ssin the range of 10～15 mg/L and 15～20 mg/L were 51.2%and 40.6%respectively.The series of optimal dosing regimens recommended by the model had an good average PTA over 71%for C_sswithin the range of 10～20 mg/L.（3）It was found that the prediction error of the model was small,when applying this model combined with Bayesian feedback method to guide individualized vancomycin dosing regimen and adjusted dosing regimen for clinical cases.And the prediction error was smaller than that of the previous vancomycin PPK model with CLcr as the renal function covariate.Conclusions:（1）Renal function,age,and body weight are the main factors affecting vancomycin clearance.As the GFR decreases,age increases and body weight loses,vancomycin clearance rate decreases.No obvious factor was found to have effect on the apparent distribution of vancomycin.The vancomycin PPK model established in this study had a good stability and predictability,which can be used to guide individualized vancomycin dosing regimen for clinical.（2）There was a good PTA for the optimal dosing regimens of different renal function levels based on the model simulation,and the recommended dosing regimens can provide important references for clinical application.（3）It had a good effectiveness and practicability to implement individualized vancomycin dosing regimens for clinical cases through this PPK model,and it was superior to the previous model that use CLcr as the renal function covariate,which helps to promote the implementation of individualized dosing regimens in clinical more accurately.