Jirasiritham S, Sumethkul V, Mavichak V, Na-Bangchang K
Ramathibodi Hospital, Bangkok, Thailand.
Transplant Proc. 2004 Sep;36(7):2076-8. doi: 10.1016/j.transproceed.2004.08.087.
Mycophenolate mofetil, in addition to cyclosporine and prednisolone significantly reduces the rate of acute rejection. The original recommended dose of MMF is fixed at 2 g/day. However, Thai patients cannot tolerate this dose due to gastrointestinal adverse effects. So the majority of patients are maintained on MMF at doses ranging from 0.5 to 2 g/day, according to their tolerability with an acceptable rate of acute rejection episodes. This study sought to determine the steady state pharmacokinetics of MMF in Thai kidney transplant recipients on stable doses of MMF. Forty-six kidney transplant patients more than 3 months on a stable MMF dose of 0.5, 1, 1.5, and 2 g/day together with cyclosporine and prednisolone underwent a single pharmacokinetic blood sampling for 12 hours following the morning dose of MMF. The analysis of plasma concentrations of mycophenolic acid (MPA), the sole pharmacologically active metabolite of MMF, was performed by using an high performance liquid chromatography method. Sparse efficient sampling strategies were employed to optimize the blood sampling schedule. Hence, blood samples were collected at 0, 0.5, 2, 12 hours after the MMF dose. The sampling time was designed to best estimate AUC(0-tau) at steady state. The initial MPA-Bayesian estimator were used for MPA concentrations that would allow the best estimation of Vc, CLt, and Ka. In this study, there is a high interindividual variability in the AUC. The median MPA AUC was 34.3 ug.h/mL (range 14.1-65.4). Thirty-one of 45 (68.9%) patients had a MPA AUC within 20 to 40 ug.h/mL, which is the most reasonable risk: benefit ratio in terms of preventing acute rejection episodes. Forty-one of 45 (91.1%) patients had MPA AUC within 20 to 60 ug.h/mL, which is the MPA therapeutic range. The highest Pearson correlation coefficient of determination between MPA AUC and a single concentration was observed with MPA 2 hours (r = 0.622) Without a fixed dosing regimen, most Thai kidney transplant recipients who receive MMF as part of a maintenance immunosuppressive regimen have the MPA AUC within the therapeutic window. The single drug concentration that correlates well with the AUC is MPA at 2 hours postdose.
霉酚酸酯与环孢素和泼尼松龙联用，可显著降低急性排斥反应的发生率。霉酚酸酯最初推荐剂量为固定的2克/天。然而，泰国患者由于胃肠道不良反应无法耐受该剂量。因此，大多数患者根据其耐受性及可接受的急性排斥反应发生率，维持服用0.5至2克/天剂量的霉酚酸酯。本研究旨在确定稳定服用霉酚酸酯的泰国肾移植受者体内霉酚酸酯的稳态药代动力学。46例肾移植患者在稳定服用0.5、1、1.5和2克/天剂量的霉酚酸酯及环孢素和泼尼松龙超过3个月后，于早晨服用霉酚酸酯后进行了12小时的单次药代动力学血样采集。采用高效液相色谱法分析霉酚酸（MPA）的血浆浓度，MPA是霉酚酸酯唯一具有药理活性的代谢产物。采用稀疏高效采样策略优化血样采集计划。因此，在服用霉酚酸酯后0、0.5、2、12小时采集血样。采样时间旨在最佳估计稳态下的AUC(0-tau)。使用初始MPA-贝叶斯估计器计算MPA浓度，以便最佳估计Vc、CLt和Ka。在本研究中，AUC存在较高的个体间变异性。MPA AUC的中位数为34.3微克·小时/毫升（范围14.1 - 65.4）。45例患者中有31例（68.9%）的MPA AUC在20至40微克·小时/毫升之间，就预防急性排斥反应而言，这是最合理的风险效益比。45例患者中有41例（91.1%）的MPA AUC在20至60微克·小时/毫升之间，这是MPA的治疗范围。MPA AUC与单次浓度之间的最高皮尔逊相关系数在MPA 2小时时观察到（r = 0.622）。在没有固定给药方案的情况下，大多数接受霉酚酸酯作为维持免疫抑制方案一部分的泰国肾移植受者的MPA AUC在治疗窗内。与AUC相关性良好的单次药物浓度是给药后2小时的MPA。
