Dose tailoring of tacrolimus based on a non-linear pharmacokinetic model in children with refractory nephrotic syndrome

• Published in: International immunopharmacology 2021-09, Vol.98, p.107827, Article 107827
• Main Authors: Li, Ling, Zhu, Min, Li, De-Yi, Guo, Hong-Li, Hu, Ya-Hui, Xu, Ze-Yue, Jing, Xia, Chen, Feng, Zhao, Fei, Li, Yun-Man, Xu, Jing, Jiao, Zheng
• Format: Article
• Language: English
• Subjects: Adolescent; Chemotherapy; Child; Child, Preschool; Children; CYP3A5; Cytochrome P-450 CYP3A - genetics; Cytochrome P-450 CYP3A - metabolism; Diltiazem; Diltiazem - administration & dosage; Diltiazem - pharmacokinetics; Dosage; Drug Dosage Calculations; Drug dosages; Drug Monitoring - methods; Drug Resistance; Drug therapy; Female; Gene polymorphism; Genotype & phenotype; Humans; Immunosuppressive Agents - administration & dosage; Immunosuppressive Agents - pharmacokinetics; Kidney diseases; Laboratory tests; Male; Michaelis–Menten model; Modelling; Models, Biological; Nephrotic syndrome; Nephrotic Syndrome - blood; Nephrotic Syndrome - drug therapy; Nephrotic Syndrome - genetics; Nephrotic Syndrome - immunology; Nonlinear Dynamics; Pharmacogenomic Variants; Pharmacokinetics; Pharmacology; Polymorphism, Single Nucleotide; Population pharmacokinetics; Precision Medicine - methods; Refractory nephrotic syndrome; Retrospective Studies; Tacrolimus; Tacrolimus - administration & dosage; Tacrolimus - pharmacokinetics; Weight
• ISSN: 1567-5769; 1878-1705
• DOI: 10.1016/j.intimp.2021.107827

•Daily TAC dose covariate improved the predictive performance in linear PPK model.•The MM model fit the data better compared with the linear model.•A CYP3A5 genotype-based MM model could achieve the target C0 of TAC better.•Diltiazem increase the C0 of TAC, and it is more obvious in CYP3A5*3*3 carriers.•The target C0 of TAC can be easily achieved by tailoring the dose of diltiazem. The population pharmacokinetics (PPK) of tacrolimus (TAC) in children with refractory nephrotic syndrome (RNS) have not been well-characterized. This study aimed to investigate the significant factors affecting the TAC PPK characteristics of children with RNS and to optimize the dosing regimen. A total of 494 concentrations from 108 children were obtained from routine therapeutic drug monitoring between 2016 and 2018. Information regarding the demographic features, laboratory test results, genetic polymorphisms of CYP3A5 (rs776746) and co-therapy medications were collected. PPK analysis was performed using the nonlinear mixed-effects modelling (NONMEM) software and two modelling strategies (the linear one-compartment model and nonlinear Michaelis–Menten model) were evaluated and compared. CYP3A5 genotype, weight, daily dose of TAC and daily dose of diltiazem were retained in the final linear model. The absorption rate constant (Ka) was set at 4.48 h−1 in the linear model, and the apparent clearance (CL/F) and volume of distribution (V/F) in the final linear model were 14.2 L/h and 172 L, respectively. CYP3A5 genotype, weight and daily dose of diltiazem were the significant factors retained in the final nonlinear model. The maximal dose rate (Vmax) and the average steady-state concentration at half-Vmax (Km) in the final nonlinear model were 2.15 mg/day and 0.845 ng/ml, respectively. The nonlinear model described the pharmacokinetic data of TAC better than the linear model in children with RNS. A dosing regimen was proposed based on weight, CYP3A5 genotype and daily dose of diltiazem according to the final nonlinear PK model, which may facilitate individualized drug therapy with TAC.