Department of Pharmacy, Children's Hospital of Nanjing Medical University, Nanjing, China; School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China.
School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China; Department of Pharmacy, Shanghai Chest Hospital, Shanghai, China.
Int Immunopharmacol. 2021 Sep;98:107827. doi: 10.1016/j.intimp.2021.107827. Epub 2021 Jul 17.
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 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 (V) and the average steady-state concentration at half-Vmax (K) 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.
环孢素在难治性肾病综合征患儿中的群体药代动力学（PPK）特征尚未得到很好的描述。本研究旨在探讨影响难治性肾病综合征患儿环孢素 PPK 特征的重要因素，并优化给药方案。2016 年至 2018 年期间，从 108 例患儿的常规治疗药物监测中获得了 494 个浓度。收集了人口统计学特征、实验室检查结果、CYP3A5（rs776746）的遗传多态性和合并治疗药物的信息。采用非线性混合效应模型（NONMEM）软件进行 PPK 分析，并评估和比较了两种建模策略（线性单室模型和非线性米氏模型）。最终线性模型中保留了 CYP3A5 基因型、体重、环孢素日剂量和地尔硫卓日剂量。线性模型中吸收速率常数（Ka）设定为 4.48 h，最终线性模型中表观清除率（CL/F）和分布容积（V/F）分别为 14.2 L/h 和 172 L。CYP3A5 基因型、体重和地尔硫卓日剂量是最终线性模型中保留的重要因素。最终非线性模型中保留了最大剂量率（V）和平均稳态时半最大浓度（K）。最终非线性模型描述了 RNS 患儿环孢素的药代动力学数据优于线性模型。根据最终非线性 PK 模型，提出了一种基于体重、CYP3A5 基因型和地尔硫卓日剂量的给药方案，可能有助于个体化环孢素治疗。
