Hubner GI, Eismann R, Sziegoleit W
Department of Pharmacology and Toxicology, Martin Luther University Halle-Wittenberg, Halle/Saale, Germany.
Arzneimittelforschung. 2000 Oct;50(10):936-40. doi: 10.1055/s-0031-1300310.
There has been limited experience with routine therapeutic monitoring of mycophenolic acid (MPA; CAS 24280-93-1), which is the active metabolite of the new immunosuppressive prodrug mycophenolate mofetil (MMF; CAS 115007-34-6). MMF was introduced with recommendation for fixed oral dosing (1 g twice daily) in combination with cyclosporin A (CSA) and a glucocorticoid for the prevention of renal allograft rejection. In the course of routine CSA monitoring a MPA monitoring was performed in adult renal transplant patients receiving MMF in combination with CSA and methylprednisolone (MEP). For 30 consecutive patients with 234 plasma samples the relationship of MMF doses used and MPA plasma through levels estimated at steady state (C88 min) to clinical outcome was evaluated retrospectively. The MPA concentrations were determined with the enzyme-multiplied immunoassay technique (EMIT mycophenolic acid assay) on a Cobas Mira Plus analyzer. The within-run (n = 10) and between-run (n = 10) coefficients of variation were 3.6%, 3.5%, 3.1% and 3.6%, 5.1%, 6.7% analysing three MPA level plasma controls (1.25 mg/l, 7.5 mg/l, 12.5 mg/l), respectively. The data analysis of the MPA plasma trough levels resulted in a high variability between patients (0.3 to 3.4 mg/l) received the recommended fixed MMF dose (2 g/day). There was a higher incidence of adverse reactions with increasing MPA plasma trough levels (2.13 +/- 1.35 mg/l in 13 patients with side effects versus 1.53 +/- 0.67 mg/l in 17 patients without side effects; p < 0.001), regardless of reduction of MMF dose (1.77 +/- 0.3 g/day versus 1.89 +/- 0.2 g/day; NS), respectively. No acute rejection episodes occured under MMF administration in combination with CSA and MEP. The study shows that the to date recommended MMF dose resulted in individual, quite different MPA plasma trough levels, which were associated with incidence of side effects rather than the MMF doses. Therefore, monitoring of plasma MPA trough levels and individual dose adjustment could be helpful to reduce the incidence of adverse reactions and to increase the safety of MMF therapy.
霉酚酸（MPA；化学物质登记号24280 - 93 - 1）是新型免疫抑制前体药物霉酚酸酯（MMF；化学物质登记号115007 - 34 - 6）的活性代谢产物，对其进行常规治疗监测的经验有限。MMF被引入时建议固定口服剂量（每日2次，每次1 g），与环孢素A（CSA）和糖皮质激素联合使用，用于预防肾移植排斥反应。在对CSA进行常规监测的过程中，对接受MMF联合CSA和甲泼尼龙（MEP）治疗的成年肾移植患者进行了MPA监测。对连续30例患者的234份血浆样本进行回顾性评估，分析所使用的MMF剂量与稳态时估计的MPA血浆谷浓度（C88 min）与临床结局之间的关系。MPA浓度采用酶放大免疫分析技术（EMIT霉酚酸分析）在Cobas Mira Plus分析仪上测定。分析三个MPA水平的血浆对照品（1.25 mg/l、7.5 mg/l、12.5 mg/l）时，批内（n = 10）和批间（n = 10）变异系数分别为3.6%、3.5%、3.1%和3.6%、5.1%、6.7%。对接受推荐固定MMF剂量（2 g/天）的患者的MPA血浆谷浓度进行数据分析，结果显示患者之间存在很大差异（0.3至3.4 mg/l）。无论MMF剂量是否减少（分别为1.77±0.3 g/天和1.89±0.2 g/天；无显著性差异），随着MPA血浆谷浓度升高，不良反应发生率更高（13例有副作用患者为2.13±1.35 mg/l，17例无副作用患者为1.53±0.67 mg/l；p < 0.001）。在MMF联合CSA和MEP给药期间未发生急性排斥反应。该研究表明，迄今为止推荐的MMF剂量导致个体MPA血浆谷浓度差异很大，这些差异与副作用发生率相关，而非与MMF剂量相关。因此，监测血浆MPA谷浓度并进行个体化剂量调整可能有助于降低不良反应发生率，提高MMF治疗的安全性。
