Population Pharmacokinetics Of 6-thioguanine Nucleotides In Patients With Inflammatory Bowel Disease

Objective:To establish the PPK model of 6-thioguanine nucleotides in patients with inflammatory bowel disease and carry out the clinical medication research.Method:Collecting patients of azathioprine therapy and recording the detailed information of age,gender,body weight,liver and kidney function,inflammatory biomarkers and concomitant medications.Blood samples were collected from each patient at least one or two when the blood 6-thioguanine nucleotides concentration was considered to have reached in a steady state,and then using RP-HPLC to determine the concentration of 6-thioguanine nucleotides in the red blood cells.Nonlinear mixed effects model program was applied to construct the PPK model of 6-thioguanine nucleotides,and evaluating the fixed effects and random effects on the clearance of 6-thioguanine nucleotides.Then establishing the full amount of regression models of 6-thioguanine nucleotides by stepwise regression,and building the final model of 6-thioguanine nucleotides via the backward regression.Finally,the graphical method was used to evaluate the fit of the model,and the Bootstrap method was used to evaluate the stability and validity of the final model,and NPDE method was used to evaluate the predictive ability of the model.Result:Based on 156 trough concentrations of the 100 patients,the final model of 6-thioguanines is CL=×（WT/55.63）^θWT×θ_MSLQ^MSLQ×0);V=θv;Among them,the weight and MSLQ are the most important factors in 6-thioguanine nucleotides CL.Model fitting results reveals the goodness of the final model;The Bootstrap method shows the steady rate is 99.85%,and the estimated values of final model were in the95%CI,and the related deviations are all less than 3%.NPDE showed homogeneity of variance and a normal distribution.Conclusion:The PPK model of 6-thioguanine nucleotides in this study has satisfied stability and predictive ability,and is suitable to develop individualized dosage regimens.