Fromage Yeleen, Sayadi Hamza, Koloskoff Kevin, Marquet Pierre, Labriffe Marc, Monchaud Caroline, Woillard Jean-Baptiste
Department of Pharmacology, Toxicology and Pharmacovigilance, CHU de Limoges, Limoges, France.
Pharmacology & Transplantation, INSERM U1248, Université de Limoges, Limoges, France.
Br J Clin Pharmacol. 2025 May;91(5):1396-1408. doi: 10.1111/bcp.16374. Epub 2024 Dec 22.
Mycophenolic acid (MPA), the active component of enteric-coated mycophenolate sodium (EC-MPS), exhibits highly variable pharmacokinetics. Only a few population pharmacokinetic (popPK) models and Bayesian estimators (MAP-BE) exist for estimating MPA AUC and all in renal transplantation. This study aimed to develop a popPK model and MAP-BE for MPA AUC estimation using a limited sampling strategy (LSS) in solid organ transplant (SOT), haematopoietic stem cell (HSC) recipients and patients with autoimmune diseases (AID) on EC-MPS.
Full and sparse MPA pharmacokinetic profiles were extracted from our ISBA system, split into development (75%) and validation (25%) sets. An additional extraction was performed after the modelling process for external validation. Pharmacokinetic parameters were estimated using Monolix® (SAEM algorithm). Several absorption models (first order, transit, gamma) were compared. AUC by MAP-BE and LSS was compared to the all-sample MAP-BE AUC using Simulx®.
We included 153 PK profiles (863 concentration) from 129 patients (116 SOT and HSC, 13 AID), median [min-max] age 45 years [6-80]. A one-compartment model with double-gamma absorption and first-order elimination best fitted the data. The final model included the EC-MPS indication and inter-occasion variability on gamma rate constants. Main PK parameters (mean ± SD) were Cl/F = 4.99 ± 2.22 L/h and Vd/F = 12.60 ± 0.08 L. The optimal LSS at 20 min, 2 h and 4 h post-dose showed good performance in both validation sets (rMPE -2.67% and -4.91%; RMSE 13.55% and 13.47%).
The double-gamma absorption model provided an accurate fit. The MAP-BE offers a tool for EC-MPS dose individualization in SOT, HSC and AID patients.
肠溶型霉酚酸钠（EC-MPS）的活性成分霉酚酸（MPA）具有高度可变的药代动力学。目前仅有少数群体药代动力学（popPK）模型和贝叶斯估计器（MAP-BE）可用于估计肾移植中MPA的AUC及所有情况。本研究旨在开发一种popPK模型和MAP-BE，用于在实体器官移植（SOT）、造血干细胞（HSC）受体以及接受EC-MPS治疗的自身免疫性疾病（AID）患者中，采用有限采样策略（LSS）估计MPA的AUC。
从我们的ISBA系统中提取完整和稀疏的MPA药代动力学曲线，分为开发集（75%）和验证集（25%）。在建模过程后进行额外提取以进行外部验证。使用Monolix®（SAEM算法）估计药代动力学参数。比较了几种吸收模型（一级、转运、伽马）。使用Simulx®将MAP-BE和LSS得到的AUC与全样本MAP-BE的AUC进行比较。
我们纳入了129例患者的153条药代动力学曲线（863个浓度值）（116例SOT和HSC患者，13例AID患者），年龄中位数[最小值 - 最大值]为45岁[6 - 80岁]。具有双伽马吸收和一级消除的单室模型最能拟合数据。最终模型纳入了EC-MPS适应症以及伽马速率常数的给药间隔间变异性。主要药代动力学参数（平均值±标准差）为Cl/F = 4.99±2.22 L/h和Vd/F = 12.60±0.08 L。给药后20分钟、2小时和4小时的最佳LSS在两个验证集均表现出良好性能（rMPE分别为 - 2.67%和 - 4.91%；RMSE分别为13.55%和13.47%）。
双伽马吸收模型拟合准确。MAP-BE为SOT、HSC和AID患者的EC-MPS剂量个体化提供了一种工具。
