Noreikaitė Aurelija, Saint-Marcoux Franck, Marquet Pierre, Kaduševičius Edmundas, Stankevičius Edgaras
Institute of Physiology and Pharmacology, Medical Academy, Lithuanian University of Health Sciences INSERM UMR 850, Limoges Department of Pharmacology and Toxicology, CHU Limoges, Limoges Cedex University of Limoges, Limoges, France.
Medicine (Baltimore). 2017 Mar;96(13):e6469. doi: 10.1097/MD.0000000000006469.
The objective of the present study was to assess the effect of cyclosporine (CsA) on the pharmacokinetic parameters of mycophenolic acid (MPA), an active mycophenolate mofetil (MMF) metabolite, and to compare with the effect of everolimus (EVR).Anonymized medical records of 404 kidney recipients were reviewed. The main MPA pharmacokinetic parameters (AUC(0-12) and Cmax) were evaluated.The patients treated with a higher mean dose of CsA displayed higher MPA AUC(0-12) exposure in the low-dose MMF group (1000 mg/day) (40.50 ± 10.97 vs 28.08 ± 11.03 h mg/L; rs = 0.497, P < 0.05), medium-dose MMF group (2000 mg/day) (43.00 ± 6.27 vs 28.85 ± 11.08 h mg/L; rs = 0.437, P < 0.01), and high-dose MMF group (3000 mg/day) (56.75 ± 16.78 vs 36.20 ± 3.70 h mg/L; rs = 0.608, P < 0.05).A positive correlation was also observed between the mean CsA dose and the MPA Cmax in the low-dose MMF group (Cmax 22.83 ± 10.82 vs 12.08 ± 5.59 mg/L; rs = 0.507, P < 0.05) and in the medium-dose MMF group (22.77 ± 8.86 vs 13.00 ± 6.82 mg/L; rs = 0.414, P < 0.01).The comparative analysis between 2 treatment arms (MMF + CsA and MMF + EVR) showed that MPA AUC(0-12) exposure was by 43% higher in the patients treated with a medium dose of MMF and EVR than in the patients treated with a medium dose of MMF and CsA.The data of the present study suggest a possible CsA versus EVR influence on MMF pharmacokinetics. Study results show that CsA has an impact on the main MPA pharmacokinetic parameters (AUC(0-12) and Cmax) in a CsA dose-related manner, while EVR mildly influence or does not affect MPA pharmacokinetic parameters. Low-dose CsA (lower than 180 mg/day) reduces MPA AUC(0-12) exposure under the therapeutic window and may lead to ineffective therapy, while a high-dose CsA (>240 mg/day) is related to greater than 10 mg/L MPA Cmax and increases the likelihood of adverse events.
本研究的目的是评估环孢素（CsA）对霉酚酸（MPA，霉酚酸酯（MMF）的活性代谢产物）药代动力学参数的影响，并与依维莫司（EVR）的影响进行比较。回顾了404例肾移植受者的匿名医疗记录。评估了主要的MPA药代动力学参数（AUC(0-12)和Cmax）。在低剂量MMF组（1000mg/天）中，接受较高平均剂量CsA治疗的患者显示出较高的MPA AUC(0-12)暴露水平（40.50±10.97 vs 28.08±11.03h·mg/L；rs = 0.497，P<0.05），中剂量MMF组（2000mg/天）中（43.00±6.27 vs 28.85±11.08h·mg/L；rs = 0.437，P<0.01），以及高剂量MMF组（3000mg/天）中（56.75±16.78 vs 36.20±3.70h·mg/L；rs = 0.608，P<0.05）。在低剂量MMF组（Cmax 22.83±10.82 vs 12.08±5.59mg/L；rs = 0.507，P<0.05）和中剂量MMF组（22.77±8.86 vs 13.00±6.82mg/L；rs = 0.414，P<0.01）中，CsA平均剂量与MPA Cmax之间也观察到正相关。两个治疗组（MMF+CsA和MMF+EVR）之间的比较分析表明，接受中剂量MMF和EVR治疗的患者的MPA AUC(0-12)暴露水平比接受中剂量MMF和CsA治疗的患者高43%。本研究数据表明CsA与EVR对MMF药代动力学可能存在影响。研究结果表明，CsA以与剂量相关的方式影响主要的MPA药代动力学参数（AUC(0-12)和Cmax），而EVR对MPA药代动力学参数影响轻微或无影响。低剂量CsA（低于180mg/天）会降低治疗窗内的MPA AUC(0-12)暴露水平，可能导致治疗无效，而高剂量CsA（>240mg/天）与MPA Cmax大于10mg/L相关，增加了不良事件的发生可能性。
