Wei Yinyi, Wu Dongni, Chen Yiyu, Dong Chunqiang, Qi Jianying, Wu Yun, Cai Rongda, Zhou Siru, Li Chengxin, Niu Lulu, Wu Tingqing, Xiao Yang, Liu Taotao
Department of Pharmacy, The First Affiliated Hospital of Guangxi Medical University, Nanning, China.
Department of Organ Transplant, The First Affiliated Hospital of Guangxi Medical University, Nanning, China.
Front Pharmacol. 2022 Oct 13;13:1002628. doi: 10.3389/fphar.2022.1002628. eCollection 2022.
To investigate the factors influencing the pharmacokinetics of mycophenolate mofetil (MMF) in pediatric patients after liver transplantation, and to establish a population pharmacokinetics model, which can provide a reference for clinical dosage adjustment. A prospective study in a single center was performed on pediatric patients who were administrated with mycophenolate mofetil dispersible tablets (MMFdt) for at least 4 days after liver transplantation continuously. Blood samples were collected in ethylene diamine tetraacetic acid anticoagulant tubes before dosing and 0.5, 1, 2, 4, 8, and 12 h after the morning intake of MMFdt. The concentrations of mycophenolic acid (MPA) in plasma were assayed with a validated reverse-phase high-performance liquid chromatography method. , , , , polymorphism were determined by Sanger sequencing. Nonlinear mixed effects modeling was used to establish the population pharmacokinetics (PPK) model. The predictability and stability of the model were internally evaluated by the goodness of fit plots, visual prediction check, normalized prediction errors, and bootstraps. A two-compartment model with first-order absorption and first-order elimination was established with 115 MPA concentrations from 20 pediatric patients. The final model were: CL/F (L/h) = 14.8×(WT/7.5)×(DOSE/11.16)×е, Ka (h) = 2.02×(WT/7.5), Vc/F (L) = 6.01×(WT/7.5), Vp/F (L) = 269 (fixed), Q/F (L/h) = 15.4×(WT/7.5)×е. Where CL/F was the apparent clearance rate, Ka was the absorption rate constant, Vc/F was the apparent distribution volume of the central compartment, Vp/F was the apparent distribution volume of the peripheral compartment, Q/F was the atrioventricular clearance rate, WT was the body weight of the subject, and DOSE was the MMFdt administered dose. The model indicated there was large inter-individual variability in CL/F and Q/F after multiple dosing of MMFdt. Internal evaluation results showed that the final model had good stability and prediction performance. A stable and predictive population pharmacokinetic model of MMFdt in pediatric patients after the early stage of liver transplantation was established. The pediatric patient's weight and the dose of MMFdt can be a reference to adjust the MMFdt dose.
为研究肝移植术后小儿患者霉酚酸酯（MMF）药代动力学的影响因素，并建立群体药代动力学模型，为临床剂量调整提供参考。对单中心的小儿患者进行前瞻性研究，这些患者在肝移植术后连续至少4天服用霉酚酸酯分散片（MMFdt）。在给药前以及早晨服用MMFdt后0.5、1、2、4、8和12小时，于乙二胺四乙酸抗凝管中采集血样。采用经过验证的反相高效液相色谱法测定血浆中霉酚酸（MPA）的浓度。通过桑格测序确定……、……、……、……、多态性。采用非线性混合效应建模建立群体药代动力学（PPK）模型。通过拟合优度图、可视化预测检查、标准化预测误差和自抽样法对模型的预测性和稳定性进行内部评估。利用20例小儿患者的115个MPA浓度建立了具有一级吸收和一级消除的二室模型。最终模型为：CL/F（L/h）=14.8×（WT/7.5）×（DOSE/11.16）×е，Ka（h）=2.02×（WT/7.5），Vc/F（L）=6.01×（WT/7.5），Vp/F（L）=269（固定值），Q/F（L/h）=15.4×（WT/7.5）×е。其中CL/F为表观清除率，Ka为吸收速率常数，Vc/F为中央室的表观分布容积，Vp/F为周边室的表观分布容积，Q/F为房室清除率，WT为受试者体重，DOSE为服用的MMFdt剂量。该模型表明多次服用MMFdt后CL/F和Q/F存在较大个体间差异。内部评估结果显示最终模型具有良好的稳定性和预测性能。建立了肝移植术后早期小儿患者MMFdt稳定且具有预测性的群体药代动力学模型。小儿患者的体重和MMFdt剂量可作为调整MMFdt剂量的参考。
