Yin H, Qiu K, Hu X P, Li X B, Wang W, Liu L H, Zhang X D
Department of Urology and Kidney Transplantation, Beijing ChaoYang Hospital, Capital Medical University, Beijing, China.
Int J Clin Pract Suppl. 2014 Apr(181):31-7. doi: 10.1111/ijcp.12404.
There are few pharmacokinetic data for enteric-coated mycophenolate sodium (EC-MPS) in Chinese kidney transplant recipients. Previously, we demonstrated that patients with 540 mg EC-MPS reached target exposure on day 4 after transplantation. The aim of this study was further to confirm that mycophenolic acid (MPA) delivery with a daily total dose 1080 mg EC-MPS is adequate during the early-phase posttransplantation and preliminarily assess the pharmacokinetics after a single dose and multiple doses of EC-MPS in Chinese live-donor kidney transplant recipients.
Twelve patients (eight men and four women, mean age 41.3 ± 6.78 years) treated with EC-MPS, cyclosporine and corticosteroids were included in this study. Patients received a single oral dose of EC-MPS 540 mg, then 540 mg twice daily. MPA concentrations were measured by high-performance liquid chromatography. Twelve-hour pharmacokinetic profiles were obtained after the single oral dose and multiple doses on day 4 postoperation. The pharmacokinetic parameters were compared between a single dose and multiple doses. By using multiple stepwise regression analysis, we obtained two predictive equations of MPA systemic exposure. Bland-Altman analysis was developed to test agreement between the observed MPA area under the concentration-time curve (AUC) and the predicted MPA AUC.
The mean (range) MPA AUC was 42 ± 14.67 (29.29-75.95) mg/l h after the first dose, and 44.72 ± 14.57 (32.06-80.79) mg/l h on day 4 after operation. MPA exposure provided by a single dose and multiple doses were similar (p > 0.05). The best equations obtained were the following: 20.003 + 1.181C6 h + 7.22C8 h (r = 0.936) and 17.023 + 3.11C1 h + 1.245 + 4.988C8 h (r = 0.964). These equation models showed an optimal agreement between the observed MPA AUC and the predicted MPA AUC.
Lower dosing of EC-MPS, compared with the standard dose (720 mg twice daily), may provide enough MPA exposure for Chinese live-donor kidney transplant patients on day 4. Given that the MPA exposure by AUC correlates with the incidence of acute rejection episodes and transplant vasculopathy, the present findings may have clinical implications, and the optimum dose range of EC-MPS for patients in all ranges of body weight should also be determined.
在中国肾移植受者中，肠溶包衣的麦考酚钠（EC-MPS）的药代动力学数据较少。此前，我们证明接受540mg EC-MPS的患者在移植后第4天达到目标暴露量。本研究的目的是进一步确认每日总剂量1080mg EC-MPS在移植后早期阶段提供的麦考酚酸（MPA）剂量是足够的，并初步评估中国活体供肾移植受者单次和多次服用EC-MPS后的药代动力学。
本研究纳入12例接受EC-MPS、环孢素和皮质类固醇治疗的患者（8例男性和4例女性，平均年龄41.3±6.78岁）。患者先口服单次剂量540mg EC-MPS，然后每日两次，每次540mg。采用高效液相色谱法测定MPA浓度。在单次口服剂量后以及术后第4天多次给药后获得12小时的药代动力学曲线。比较单次剂量和多次剂量的药代动力学参数。通过多元逐步回归分析，我们获得了两个MPA全身暴露的预测方程。采用Bland-Altman分析来检验观察到的MPA浓度-时间曲线下面积（AUC）与预测的MPA AUC之间的一致性。
首次给药后MPA AUC的平均值（范围）为42±14.67（29.29 - 75.95）mg/l·h，术后第4天为44.72±14.57（32.06 - 80.79）mg/l·h。单次剂量和多次剂量提供的MPA暴露相似（p>0.05）。得到的最佳方程如下：20.003 + 1.181C6 h + 7.22C8 h（r = 0.936）和17.023 + 3.11C1 h + 1.245 + 4.988C8 h（r = 0.964）。这些方程模型显示观察到的MPA AUC与预测的MPA AUC之间具有最佳一致性。
与标准剂量（每日两次，每次720mg）相比，较低剂量的EC-MPS可能在术后第4天为中国活体供肾移植患者提供足够的MPA暴露。鉴于MPA AUC的暴露与急性排斥反应发作和移植血管病变的发生率相关，目前的研究结果可能具有临床意义，并且还应确定所有体重范围内患者的EC-MPS最佳剂量范围。
