Study On Population Pharmacokinetics Model Of Sirolimus In Renal Transplantation Patients

OBJECTIVETo construct a population pharmacokinetics(PPK)model of sirolimus in Chinese renal transplantation patients,and to study the pharmacological characteristics and influencing factors of sirolimus.To provide theory support for personalized drug use.METHODS111 renal transplantation patients,who were orally administrated with sirolimus after transplantation,were enrolled in the study.Retrospectively collected blood concentrations of sirolimus and related laboratory test results.According to clinical needs,the patients after transplant surgery were collected peripheral venous blood before oral sirolimus therapy.Abbott ARCHITECT i1000SR were used to determine steady state trough blood concentrations of sirolimus.The influence of demographic characteristics(including gender,age,weight),biochemical and haematological indices(including hematocrit,hemoglobin,red blood cell count,white blood cell count,platelet count,blood urea nitrogen,serum creatinine,glucose,alanine transaminase,aspartate transaminase,lactate dehydrogenase,alkaline phosphatase,gamma glutamyl transpeptidase,triglycerides,total cholesterol,high-density lipoprotein cholesterol,low-density lipoprotein cholesterol,total bilirubin,direct bilirubin,indirect bilirubin,albumin,uric acid),and other commonly used co-medications which may affect the pharmacological characteristics of sirolimus were explored.Effects of weight,age,gender,drug dose,drug combination,liver and kidney function on pharmacokinetic parameter were analyzed by Phoenix NLME.Performance of final model was internally assessed by bootstrapping and visual predictive checking(VPC).RESULTSA one-compartment model with first-order elimination pharmacokinetics provided the best fitting.Hematocrit influenced the clearance of sirolimus,alkaline phosphatase influenced volume of distribution.Typical value of CL/F was 10.8 L·h-1,typical value of V/F was 1011L.Stability and predictive performance were accepted by goodness-of-fit,bootstrapping and VPC.CONCLUSIONA PPK model of sirolimus in Chinese renal transplantation patients is successfully established in this study.Effects of weight,age,gender,drug dose,drug combination,liver and kidney function on pharmacokinetic parameter were inspected.Hematocrit influenced the clearance of sirolimus,alkaline phosphatase influenced volume of distribution.It is of great significance for clinical rational drug use of sirolimus.