Department of Clinical Pharmacy and Education, Graduate School of Pharmaceutical Science, Kyoto University, Sakyo-ku, Kyoto, Japan.
Department of Clinical Pharmacology and Therapeutics, Kyoto University Hospital, Sakyo-ku, Kyoto, Japan.
Bone Marrow Transplant. 2018 Jan;53(1):44-51. doi: 10.1038/bmt.2017.213. Epub 2017 Oct 9.
Mycophenolate mofetil (MMF), a prodrug of mycophenolic acid (MPA), is used to suppress GvHD in patients undergoing hematopoietic stem cell transplantation (HCT). The purpose of this study was to construct a population pharmacokinetic and pharmacodynamic model in HCT patients for individualized MPA therapy. Blood samples were obtained from 49 HCT patients after starting MMF therapy. Population pharmacokinetic and pharmacodynamic parameters were obtained using the program NONMEM. MPA was described via a one-compartment model with a first-order elimination, and 30.9% of MPA glucuronide (MPAG) was found in the enterohepatic circulation. Inosine-5'-monophosphate dehydrogenase (IMPDH) activity was modeled as a maximal inhibitory model with a half-maximal inhibitory concentration (IC) of 3.59 μg/mL against MPA concentrations. Simulations based on the obtained pharmacokinetic and pharmacodynamic parameters revealed that decreased creatinine clearance increases the MPAG concentration followed by an increased MPA concentration; therefore, IMPDH activity decreases. Diarrhea decreases the enterohepatic circulation of MPAG and consequently reduces MPA concentration. The IC for MPA exhibited a positive association with C-reactive protein. Dosage adjustment based on plasma MPA concentration is required especially for patients with renal dysfunction and/or diarrhea.
霉酚酸酯（MMF）是霉酚酸（MPA）的前体药物，用于抑制接受造血干细胞移植（HCT）的患者的移植物抗宿主病（GvHD）。本研究的目的是为 HCT 患者建立 MPA 个体化治疗的群体药代动力学和药效动力学模型。在开始 MMF 治疗后，从 49 名 HCT 患者中采集血样。使用 NONMEM 程序获得群体药代动力学和药效动力学参数。MPA 通过具有一级消除的单室模型进行描述，并且在肠肝循环中发现 30.9%的 MPA 葡萄糖醛酸酯（MPAG）。肌苷-5'-单磷酸脱氢酶（IMPDH）活性被建模为具有半最大抑制浓度（IC）为 3.59μg/mL 的最大抑制模型，对抗 MPA 浓度。基于获得的药代动力学和药效动力学参数的模拟表明，肌酐清除率降低会增加 MPAG 浓度，随后 MPA 浓度增加；因此，IMPDH 活性降低。腹泻会减少 MPAG 的肠肝循环，从而降低 MPA 浓度。MPA 的 IC 与 C-反应蛋白呈正相关。特别是对于肾功能不全和/或腹泻的患者，需要根据血浆 MPA 浓度调整剂量。
