Abstract

1. We aimed to establish a population pharmacokinetic (PK) model of tacrolimus and identify clinical covariates, especially the genetic polymorphisms of CYP3A5, ABCB1 and POR*28 that affected the PK to prevent fluctuation in the trough concentration of tacrolimus during the early period after renal transplantation.

2. Tacrolimus trough concentration, clinical data and CYP3A5/ABCB1/POR28 genotypes were retrospectively collected from 234 kidney transplant recipients during the first month post-transplantation. The population PK model was built using the non-linear mixed effects modeling software NONMEM. Dosing simulation was performed based on the final model.

3. A one-compartment model with first-order absorption and elimination was used to characterize the PK of tacrolimus. Among the genotypes, only CYP3A5 genotype was confirmed to have clinical significance. The final model describing CL/F (l/h) was as follows:

$23.3{\times \left(\mathit{HCT}/0.309\right)}^{-0.445}\mathrm{ }\times \left[(0.897,\mathrm{ }if \mathit{POD} >10)or (1,if \mathit{POD} \le 10)\right]\times (0.657,if \mathit{CYP}3A5*3/*3 \mathit{genotype}).$ The inter-individual variability in CL/F was 21.9%. Monte Carlo simulation based on the final model was carried out to determine the optimal dosage regimen.

4. CYP3A5 genotype, post-operative day and hematocrit were confirmed as critical PK factors of tacrolimus. The model could be used to accurately predict individual PK parameters of tacrolimus and provide valuable insights into the dosage optimization.

摘要

1.我们的目标是建立他克莫司的群体药代动力学（PK）模型并鉴定临床协变量，尤其是CYP3A5，ABCB1和POR * 28的遗传多态性，影响该PK，以防止他克莫司的谷浓度在之后的早期波动。肾移植。

2.在移植后的第一个月内，从234名肾移植受者中回顾性收集了他克莫司谷浓度，临床数据和CYP3A5 / ABCB1 / POR28基因型。人口PK模型是使用非线性混合效应建模软件NONMEM建立的。基于最终模型进行剂量模拟。

3.使用具有一阶吸收和消除的单室模型表征他克莫司的PK。在这些基因型中，仅CYP3A5基因型被证实具有临床意义。描述CL / F（l / h）的最终模型如下：

$23.3{\times （\mathit{HCT}/0.309）}^{-0.445}\mathrm{ }\times \left[（0.897，\mathrm{ }\mathrm{一世}F \mathit{荚} >10）Ø\mathrm{[R} （\mathrm{1个}，\mathrm{一世}F \mathit{荚} \le 10）\right]\times （0.657，\mathrm{一世}F \mathit{CYP}3\mathrm{一种}5*3/*3 \mathit{基因型}）。$CL / F的个体间差异为21.9％。进行基于最终模型的蒙特卡洛模拟，以确定最佳剂量方案。

4. CYP3A5基因型，术后日和血细胞比容被确认为他克莫司的关键PK因子。该模型可用于准确预测他克莫司的各个PK参数，并为剂量优化提供有价值的见解。