Chen Hao, Gu Zhidong, Chen Bing, Mao Huarong, Zhang Weixia, Fan Qishi
Center of Organ Transplantation, Ruijin Hospital, Shanghai Jiaoton University School of Medicine, Shanghai, People's Republic of China.
Clin Ther. 2008 Dec;30(12):2387-401. doi: 10.1016/j.clinthera.2008.12.017.
An enzyme multiplied immunoassay technique (EMIT) provides convenient and accurate measurements of mycophenolic acid (MPA) concentrations for determination of immunosuppression during treatment with mycophenolate mofetil (MMF). No abbreviated model for estimating the full 12-hour MPA AUC using an EMIT assay in liver transplant recipients has been described previously.
This study was conducted to determine the best model for predicting the MPA AUC using the EMIT method and a limited-sampling strategy in Chinese patients undergoing liver transplantation.
The study enrolled consecutive liver transplant patients who were receiving MMF 1 g BID along with tacrolimus. A complete MPA pharmacokinetic profile was obtained for each patient on a single day, 7 to 14 days after transplantation. The EMIT method was used to determine MPA concentrations before dosing and at 0.5, 1, 1.5, 2, 4, 6, 8, 10, and 12 hours after dosing on the sampling day. Multiple linear regression analysis was used to evaluate potential models for estimating the full 12-hour MPA AUC. The accuracy and robustness of the models were evaluated using bootstrap analysis. Prediction error and prediction bias were calculated. Agreement between the estimated MPA AUC(0-12) and the full 12-hour MPA AUC was investigated using Bland-Altman analysis.
The study enrolled 48 Chinese liver transplant recipients (45 male, 3 female) with a mean (SD) age of 50 (12) years, mean weight of 64 (12) kg, and mean height of 169 (6) cm. Twenty-four models that included blood sampling at 1 through 4 time points were developed (r(2) = 0.015-0.950). Four models with the highest r(2) values were selected; the lack of significant differences from the original dataset on bootstrap analysis indicated acceptable accuracy and robustness. The best model for predicting the MPA AUC(0-12) employed concentrations at 1, 2, 4, and 8 hours; 40 of 48 (83.3%) MPA AUC(0-12) values estimated using this model were within 15% of the full 12-hour MPA AUC. This model had a minimal mean prediction error (mean [SD], 0.27% [1.79%]) and mean absolute prediction error (8.83% [1.24%]). On Bland-Altman analysis, this model also had the best agreement between the estimated MAP AUC(0-12) and the full 12-hour MPA AUC, with a mean error of 9.02 mg . h/L.
In this small group of Chinese liver transplant patients receiving MMF and concomitant tacrolimus, models for estimating the MPA AUC(0-12) were developed using the EMIT method and a limited-sampling strategy. The best model for prediction of the full 12-hour MPA AUC was 4.46 + 0.81 . C1 + 1.78 . C(2)+2.51.C(4)+4.94.C8.
酶放大免疫分析技术（EMIT）为测定霉酚酸酯（MMF）治疗期间的免疫抑制作用提供了便捷、准确的霉酚酸（MPA）浓度测量方法。此前尚未有关于使用EMIT法估算肝移植受者完整12小时MPA曲线下面积（AUC）的简化模型的报道。
本研究旨在确定在中国接受肝移植的患者中，使用EMIT法和有限采样策略预测MPA AUC的最佳模型。
本研究纳入了连续接受MMF 1 g每日两次联合他克莫司治疗的肝移植患者。在移植后7至14天的某一天，为每位患者获取完整的MPA药代动力学资料。采用EMIT法在给药前以及采样日给药后0.5、1、1.5、2、4、6、8、10和12小时测定MPA浓度。采用多元线性回归分析评估估算完整12小时MPA AUC的潜在模型。使用自抽样分析评估模型的准确性和稳健性。计算预测误差和预测偏差。采用Bland - Altman分析研究估算的MPA AUC(0 - 12)与完整12小时MPA AUC之间的一致性。
本研究纳入了48例中国肝移植受者（45例男性，3例女性），平均（标准差）年龄为50（12）岁，平均体重为64（12）kg，平均身高为169（6）cm。建立了24个包含在1至4个时间点采血的模型（r(2)=0.015 - 0.950）。选择了4个r(2)值最高的模型；自抽样分析显示与原始数据集无显著差异，表明准确性和稳健性可接受。预测MPA AUC(0 - 12)的最佳模型采用1、2、4和8小时的浓度；使用该模型估算的48例MPA AUC(0 - 12)值中有40例（83.3%）在完整12小时MPA AUC的15%范围内。该模型的平均预测误差最小（平均[标准差]，0.27% [1.79%]），平均绝对预测误差为8.83% [1.24%]。在Bland - Altman分析中，该模型在估算的MAP AUC(0 - 12)与完整12小时MPA AUC之间也具有最佳一致性，平均误差为9.02 mg·h/L。
在这一小群接受MMF和联合他克莫司治疗的中国肝移植患者中，采用EMIT法和有限采样策略建立了估算MPA AUC(0 - 12)的模型。预测完整12小时MPA AUC的最佳模型为4.46 + 0.81·C1 + 1.78·C(2)+2.51·C(4)+4.94·C8。
