Zhou Pei-Jun, Xu Da, Yu Zi-Cheng, Wang Xiang-Hui, Shao Kun, Zhao Ju-Ping
Division of Kidney Transplantation, Department of Urology, Rui-Jin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, P.R. China.
Clin Pharmacokinet. 2007;46(5):389-401. doi: 10.2165/00003088-200746050-00002.
To investigate the pharmacokinetics of mycophenolic acid (MPA) in Chinese adult renal allograft recipients, and to generate the validated model equations for estimation of the MPA area under the plasma concentration-time curve from 0 to 12 hours (AUC(12)) with a limited sampling strategy.
The pharmacokinetics in 75 Chinese renal allograft recipients treated with mycophenolate mofetil 2 g/day in combination with cyclosporin and corticosteroids were determined. The MPA concentration was assayed by high-performance liquid chromatography at pre-dose (C(0)) and at 0.5 (C(0.5)), 1 (C(1)), 1.5 (C(1.5)), 2 (C(2)), 4 (C(4)), 6 (C(6)), 8 (C(8)), 10 (C(10)) and 12 (C(12)) hours after dosing on day 14 post-transplant. Patients were randomly divided into: (i) a model group (n = 50) to generate the model equations by multiple stepwise regression analysis for estimation of the MPA AUC by a limited sampling strategy; and (ii) a validation group (n = 25) to evaluate the predictive performance of the model equations.
The mean MPA AUC(12) was 52.97 +/- 15.09 mg . h/L, ranging from 24.0 to 102.3 mg . h/L. The patient's age and serum albumin level had a significant impact on the MPA AUC(12). The correlation between the pre-dose MPA trough level (C(0)) and the MPA AUC(12) was poor (r(2) = 0.02, p = 0.33). Model equations 7 (MPA AUC(12) = 14.81 + 0.80 . C(0.5) + 1.56 . C(2) + 4.80 . C(4), r(2) = 0.70) and 11 (MPA AUC(12) = 11.29 + 0.51 . C(0.5) + 2.13 . C(2) + 8.15 . C(8), r(2) = 0.88) were selected for MPA AUC calculation in Chinese patients, resulting in good agreements between the estimated MPA AUC and the full MPA AUC(12), with a mean prediction error of +/-10.1 and +/-6.9 mg . h/L, respectively.
In Chinese renal allograft recipients, MPA pharmacokinetics manifest substantial interindividual variability, and the MPA AUC(12) tends to be higher than that in Caucasian patients receiving the same dose of mycophenolate mofetil. Two validated model equations with three sampling timepoints are recommended for MPA AUC estimation in Chinese patients.
研究霉酚酸（MPA）在中国成年肾移植受者中的药代动力学，并通过有限采样策略生成用于估算MPA血浆浓度 - 时间曲线下0至12小时面积（AUC(12)）的验证模型方程。
测定了75例接受霉酚酸酯2 g/天联合环孢素和皮质类固醇治疗的中国肾移植受者的药代动力学。在移植后第14天给药前（C(0)）以及给药后0.5（C(0.5)）、1（C(1)）、1.5（C(1.5)）、2（C(2)）、4（C(4)）、6（C(6)）、8（C(8)）、10（C(10)）和12（C(12)）小时，通过高效液相色谱法测定MPA浓度。患者被随机分为：（i）模型组（n = 50），通过多步逐步回归分析生成模型方程，以通过有限采样策略估算MPA AUC；（ii）验证组（n = 25），评估模型方程的预测性能。
MPA的平均AUC(12)为52.97±15.09 mg·h/L，范围为24.0至102.3 mg·h/L。患者年龄和血清白蛋白水平对MPA AUC(12)有显著影响。给药前MPA谷浓度（C(0)）与MPA AUC(12)之间的相关性较差（r(2) = 0.02，p = 0.33）。选择模型方程7（MPA AUC(12) = 14.81 + 0.80·C(0.5) + 1.56·C(2) + 4.80·C(4)，r(2) = 0.70）和11（MPA AUC(12) = 11.29 + 0.51·C(0.5) + 2.13·C(2) + 8.15·C(8)，r(2) = 0.88）用于计算中国患者的MPA AUC，估算的MPA AUC与完整的MPA AUC(12)之间具有良好的一致性，平均预测误差分别为±10.1和±6.9 mg·h/L。
在中国肾移植受者中，MPA药代动力学表现出显著的个体间差异，且MPA AUC(12)往往高于接受相同剂量霉酚酸酯的白种人患者。推荐使用两个具有三个采样时间点的验证模型方程来估算中国患者的MPA AUC。
