Tacrolimus Population Pharmacokinetics Study In Adult Nephrotic Syndrome Patients Of A Top Tertiary Hospital In Xinjiang

Objective:To investigate the influencing factors of tacrolimus trough concentration in adult patients with Nephrotic syndrome and to establish a population pharmacokinetic model,which will help individualized administration of tacrolimus in patients with nephrotic syndrome.Methods:Inquired 166 patients with Nephrotic syndrome,who met the exclusion criteria,were collected from January 2018 to December 2019 in the First Affiliated Hospital of Xinjiang Medical University.Among them,126 cases were modeling data sets and 40 cases were verification data sets and collected patients information:non-genetic data including basic patient information,laboratory test and combined drugs,genetic data including CYP3A5*3,CYP3A4?*1B,*18B,*22,*1G?,ABCB1?rs1128503and rs1045642?,NR1I2?rs3814055,rs2276707 and rs6785049?,SUMO4 rs237025 and POR*28 genotypes.For data analysis,firstly the influencing factors of tacrolimus steady-state trough concentration were screened by univariate analysis,and then set up a tacrolimus dose-adjusted trough concentration prediction model by multiple linear regression,lastly NONMEM method was used to establish apparent clearance mode for population pharmacokinetic analysis.Prediction error test was used as a unified method for two models comparison,and the optimal model was selected to formulate the initial TAC dose plan and then adopt external validation.Results:1 Univariate analysis showed that ethnic,nifedipine,lansoprazole,urea nitrogen,uric acid,alanine transaminase,total protein,albumin,and CYP3A5*3 gene polymorphisms were significantly related to tacrolimus trough concentrations in steady state?P<0.05?.2 The predictive model of tacrolimus dose-adjusted trough concentration established by multiple linear regression methodis Y(lg₁₀C^ss_min/D)=1.720+0.148CYP3A5*3+0.013BMI-0.054Gender+0.144×CYP3A4*22+0.078co-administration of Wuzhi capsule.3 The population pharmacokinetic model is:CL/F(L/h^-1)=20.9·?_Wuzhi·?_CYP3A5·e^0.285(ifco-administrationofWuzhi capsule,?_WuzhiI=0.731,otherwise?_Wuzhi=1.if CYP3A5*3*3,?_CYP3A5=0.768,otherwise?_CYP3A5=1),the results showed that CYP3A5*3 polymorphisms and Wuzhi capsules are significantly correlated with tacrolimus clearance.4 The internal validation results showed that the population pharmacokinetic model was superior to the multiple linear regression model,so the optimal population pharmacokinetic model was used for the initial TAC dosage design.When target concentration is set to 7.5ng/mL,the initial administration scheme was determined as followed.Patients who carried CYP3A5*1*1/*1*3 genotype and*3*3 genotype,the initial TAC dose was 2.0mg and 1.5mg per 12h respectively.Patients who co-administrated receiving Wuzhi capsules should be given1.5mg per 12h regardless of the CYP3A5 genotype.The program verification compliance rate was 76.9%.Conclusion:This study found that a variety of factors affect the steady-state trough concentration of tacrolimus,of which the effects of Wuzhi capsules and CYP3A5*3 are relatively clearer;and based on a population pharmacokinetic model that is superior to multiple linear regression models to make an initial TAC dosage design which with a high coincidence rate of external verification,so that this study laid a foundation for the individualized administration of tacrolimus for patients with nephrotic syndrome in our hospital.