Population Pharmacokinetics Of Leflunomide In Chinese Healthy Volunteers

Objective:To develop a population pharmacokinetic model of leflunomide in Chinese healthy volunteers and evaluate the effect of individual factors on the pharmacokinetics of leflunomide.Then,providing the reference information for leflunomide clinical individualized medicine.Methods:1)Building a quantitative analysis method of leflunomide active metabolite teriflunomide in the Chinese healthy volunteer plasma by high performance liquid chromatography-tandem mass spectrometry?HPLC/MS/MS?.Then,verifying the specificity,accuracy,precision,stability and recovery of the method.2)Collecting and filtering the healthy volunteer who satisfies the inclusion and exclusion criteria.After informed consent,collect plasma samples according to the technical guidelines for the study of human bioavailabilityl,and collect its physiological information?age,high,weight,BMI,etc.?and laboratory examinations index?TBIL,ALT,AST,GGT,ALP,BUN,Cr,etc.?.Then,detecting the leflunomide active metabolite teriflunomide plasma concentration.3)Phoenix NLME?Vision 8.0?software was used to establish the leflunomide population pharmacokinetics model in Chinese healthy volunteer by teriflunomide plasma concentration,physiological information and laboratory examinations index.Then,assessing the influence of physiological information on pharmacokinetic characters of leflunomide active metabolite teriflunomide.Finally,ensure the final model stable and reliable by Bootstrap and VPC.Results:1)In this study,the quantitative analysis method of detection teriflunomide plasma concentrations in Chinese healthy volunteer by HPLC/MS/MS were established successfully.The specificity,accuracy,precision,stability and recovery of this method meet requirements,and the results are accurate and stabilized.2)A total of 21 healthy male subjects were enrolled in this study.The average physiological information of age,high,weight and BMI were 22.59±2.04 years old,1.72±0.05 m,64.43±6.49 kg and21.72±1.64 in the rest of the patients.3)One-compartment model with first order absorption was fitted to the leflunomide active metabolite teriflunomide concentration data.The population value of k_a,V,CL were 0.691h^-1?12.843L and 0.031L·h^-1,respectively.In the model,the correlation of individual predicted and observed of teriflunomide,and there were not significance bias between population predicted and time with conditions of weighted residuals?CWRES?.The most difference of concentration prediction in the standard deviation with 2 times.It proved the prediction effect of basic model is very well.The V was found to be significantly related to the covariate of BMI?P<0.01?.Conclusion:1)In this study,the quantitative analysis method of detection leflunomide active metabolite teriflunomide plasma concentrations in Chinese healthy volunteer by HPLC/MS/MS were established successfully.The specificity,accuracy,precision,stability and recovery of this method meet requirements,and the results are accurate and stabilized.2)The population pharmacokinetics model of leflunomide in Chinese healthy volunteer was established successfully in this study,and the diagnosis of the model was well.The final model could be used to provide accurate individual pharmacokinetic parameters.V was significantly influenced of BMI by the covariate,which showed that it is better to administer drug according individual BMI in clinical practice.