Study On The Pharmacokinetics Of Commonly Used Calcineurin Inhibitors In Different Populations

OBJECTIVE:1.A population pharmacokinetics model of tacrolimus was developed in liver transplantation patients to study the effects of percentage body fat（PBF）on the pharmacokinetics of tacrolimus in liver transplantation recipients and to guide rational drug use in clinic.2.A population pharmacokinetics model of Cs A was developed in allogeneic hematopoietic stem cell transplantation patients and to design a limited sampling strategy to optimize Cs A treatment in allogeneic hematopoietic stem cell transplantation patients.METHODS:1.Impact of PBF on pharmacokinetics of tacrolimus in liver transplantation recipients.Body composition was measured in 80 patients who underwent liver transplantation at Tianjin First Central Hospital,China,between 2015 and 2018.Blood concentration of tacrolimus were collected from therapeutic drug monitoring data.Pharmacokinetic model fitting and bayesian estimation were performed using nonlinear mixed effects modeling（NONMEM）and SPSS was used to examine the effect of PBF on tacrolimus pharmacokinetics.2.Development of population pharmacokinetics model of Cs A and design of limited sampling points in patients with allogeneic hematopoietic stem cell transplantation.Cs A plasma concentrations of 28 patients who undergoing allogeneic hematopoietic stem cell transplantation and taking Cs A to prevent or treat graft versus host disease（GVHD）in the Department of Hematology of Tianjin First Central Hospital were used to performed a PPK model and was validated using the NONMEM program,then Bayesian feedback was performed and a limited sampling points design was developed for the plasma concentration data obtained from the feedback,and regression equations for the combination of AUC and plasma concentrations of Cs A at different time points were established by multivariate linear regression analysis to diagnose the predictive power of these regression equations.RESULTS:1.Impact of PBF on pharmacokinetics of tacrolimus in liver transplantation recipients.The apparent volume of distribution（V/F）and clearance（CL/F）of tacrolimus were179L and 15.4L/h,respectively.In liver transplantation recipients with PBF≥30%,the apparent V/F of tacrolimus is lower than that in liver transplantation recipients with PBF<30%at one week after liver transplantation.2.Development of population pharmacokinetics model of Cs A and design of limited sampling points in patients with allogeneic hematopoietic stem cell transplantation.The apparent clearance（CL）and inter-individual variation of Cs A were 8.82 L/h and 25.7%,respectively.The apparent volume of distribution（V）and inter-individual variation of Cs A were 551 L and 43.2%,respectively.The results of covariate screening showed that body weight（WT）,postoperative time（POD）,and combination of voriconazole had significant effects on CL of Cs A,postoperative time（POD）,platelet（PLT）,white blood cell count（WBC）,and combination with voriconazole had significant effects on V of Cs A.In the regression equation,the deviations and absolute deviations of the two-point combination C₀ and C₆,C₂ and C₆,the three-point combination C₀,C₂ and C₆,and C₀,C₂ and C₈ are less than 15%.CONCLUSION:1.A reliable and stable model was established to describe the PPK of tacrolimus in patients receiving liver transplantation,and found that the apparent V/F of tacrolimus in liver transplantation recipients with PBF≥30%is lower than that in liver transplantation recipients with PBF<30%at one week after liver transplantation.Due to the serious adverse reactions of tacrolimus,in clinical practice,an effective dosage adjustment of tacrolimus may need to be considered in patients with PBF≥30%at one week after liver transplantation.2.A reliable and stable model was established to describe the PPK of Cs A in patients receiving allogeneic hematopoietic stem cell transplantation.According to Bayesian estimation,the area under the plasma concentration-time curve of Cs A for patients receiving allogeneic hematopoietic stem cell transplantation can be estimated using only two plasma concentration points（0,6h）with a deviation of 0.1%and an accuracy of 1%.