Department of Pharmacology and Toxicology, CHU Dupuytren, Limoges, France.
Department of Clinical Haematology and Cell Therapy, CHU Dupuytren, Limoges, France.
Br J Clin Pharmacol. 2020 Aug;86(8):1550-1559. doi: 10.1111/bcp.14261. Epub 2020 Feb 28.
Intravenous mycophenolate mofetil (IV MMF), a prodrug of mycophenolic acid (MPA), is used during nonmyeloablative and reduced-intensity conditioning haematopoetic stem cell transplantation (HCT) to improve engraftment and reduce graft-versus-host disease. The aims of this study were to develop population pharmacokinetic models and Bayesian estimators based on limited sampling strategies to allow for individual dose adjustment of intravenous mycophenolate mofetil administered by infusion in haematopoietic stem cell transplant patients.
Sixty-three MPA concentration-time profiles (median [min-max] = 6 [4-7] samples) were collected from 34 HCT recipients transplanted for 14 (1-45) days and administered IV MMF every 8 hours, concomitantly with cyclosporine. The database was split into development (75%) and validation (25%) datasets. Pharmacokinetic models characterized by a single compartment with first-order elimination, combined with two gamma distributions to describe the transformation of MMF into mycophenolic acid, were developed using in parallel nonparametric (Pmetrics) and parametric (ITSIM) approaches. The performances of the models and the derived Bayesian estimators were evaluated in the validation set.
The best limited sampling strategy led to a bias (min, max), root mean square error between observed and modeled interdose areas under the curve in the validation dataset of -11.72% (-31.08%, 5.00%), 14.9% for ITSIM and -2.21% (-23.40%, 30.01%), 12.4% for Pmetrics with three samples collected at 0.33, 2 and 3 hours post dosing.
Population pharmacokinetic models and Bayesian estimators for IV MMF in HCT have been developed and are now available online (https://pharmaco.chu-limoges.fr) for individual dose adjustment based on the interdose area under the curve.
静脉注射吗替麦考酚酯（IV MMF）是霉酚酸（MPA）的前体药物，用于非清髓性和强度降低的造血干细胞移植（HCT）中，以改善植入和减少移植物抗宿主病。本研究的目的是开发基于有限采样策略的群体药代动力学模型和贝叶斯估计器，以允许根据 HCT 患者静脉注射 MMF 的曲线下面积进行个体剂量调整。
从 34 名接受 HCT 移植的患者中收集了 63 个 MPA 浓度-时间曲线（中位数[最小-最大] = 6 [4-7]个样本），这些患者接受 HCT 移植 14（1-45）天，每 8 小时静脉注射 MMF，同时给予环孢素。数据库分为开发（75%）和验证（25%）数据集。使用并行非参数（Pmetrics）和参数（ITSIM）方法开发了具有单室一阶消除的药代动力学模型，同时结合了两个伽马分布来描述 MMF 向 MPA 的转化。在验证集中评估了模型和衍生的贝叶斯估计器的性能。
最佳的有限采样策略导致验证数据集中观察到的和模型化的剂量间 AUC 的偏差（最小，最大），根均方误差分别为 -11.72%（-31.08%，5.00%），ITSIM 为 14.9%，Pmetrics 为 -2.21%（-23.40%，30.01%），12.4%，采集 3 个样本，时间分别为给药后 0.33、2 和 3 小时。
已经开发了 HCT 中 IV MMF 的群体药代动力学模型和贝叶斯估计器，现在可以在网上（https://pharmaco.chu-limoges.fr）获得，用于根据 AUC 进行个体剂量调整。
