有限取样法估算霉酚酸在自身免疫性疾病患者的体内暴露药量  

Limited Sampling Strategy for Estimating Exposure to Mycophenolic Acid in Patients with Autoimmune Disease

作　　者：陈红君[1] 余自成[1] 周蓉[2] 唐原君[1] 黄芳华[1] 沈杰[2] 干志彬[1] 

机构地区：[1]同济大学附属杨浦医院临床药学与药理学研究室,上海200090 [2]同济大学附属杨浦医院肾内科,上海200090

出　　处：《中国药学杂志》2015年第23期2068-2072,共5页Chinese Pharmaceutical Journal

基　　金：国家自然科学基金青年项目资助项目(81302741);上海市杨浦区"百医登高"计划资助项目

摘　　要：目的建立有限取样法估算霉酚酸(MPA)在自身免疫性疾病(AID)患者的体内暴露药量(AUC)。方法24例AID患者服用霉酚酸醋(MMF)0.75 g,q12 h,达稳态后,检测服药前即刻、服药后0.5,1,1.5,2,4,6,8和12h活性代谢物MPA的血药浓度梯形法计算各例实测AUC_(0-12 h);将24例患者数据资料随机平分为模型资料组与验证资料组,对模型资料组的数据采用多元线性回归法分别拟合1~4个采血点估算AUC_(0-12 h)的数学模型对初选模型用验证资料组数据检验预测偏差和精密度,并结合临床实际情况选择最佳模型。结果 12h谷浓度建立的单点预测模型r^2值为0.957平均预测误差及绝对预测误差分别为-3.93与11.93,均<15%;0.5,1.5,6,8 h或1.5,6,8,12h四点拟合的模型与AUC_(0-12 h)的相关性均达0.996,验证后预测误差在±15%以内的例数为9例;另有2点模型与3点模型,预测效果介于上述两种模型之间。结论结合临床实际情况,精确度较高的四点模型AUC=3.19+0.49c_(0.5h)、+1.76c_(1.5h)+2.95c_(6h)+5.46c_(8h)适用于晨起服药后取血监测的住院患者;相对简便的单点模型AUC=10.82+13.37c_(12 h)适用于夜间服药次日晨起入院监测的门诊患者。Bland-Altman分析显示,两种模型均能较好预测使用MMF+甲泼尼龙二联免疫抑制方案的中国成年AID患者的MPA AUC。OBJECTIVE To establish limited sampling strategies for the estimation of exposure （AUC） to mycophenolic acid （MPA） in patients with autoimmune disease （AID）. METHODS The 24 AID patients were treated with MMF 0.75 g q12 h to steady state. Serum MPA concentrations were measured at pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8 and 12 h after dosage and MPA AUC0-12 h were caculated with the trapezoidal rule. The resulted data were randomly devided into index set and validation set. Multiple liner regression analysis of the index set was used to determine the 1 to 4 sampling estimation models and the models were validated in the validation set. The prediction bias and precision combining clinical feasibility were used to choose the final models. RESULTS The 1-point model based on the simple measurement of c12 h produced acceptable prediction for MPA AUC0-12 h, in which, r2 was 0.957, the prediction bias and imprecision were repectively -3.93 and 11.93, both 〈15%; 4-point model based on 0.5,1.5,6,8 h or 1.5,6,8,12 h sampling times were fitted to MPA AUC0-12 h, with highest correlation coefficients of 0.996, and prediction errors between±15% for 9 patients; other 2 or 3-point models resulted somewhere in-between prediction performance. CONCLUSION Considering the clinical feasibility, the accurate 4-point model AUC=3.19＋0.49c0.5 h＋1.76c1.5 h＋2.95c6 h＋5.46c8 h is applicable to MPA AUC monitoring in AID inpatients after morning dose; the simple 1-point model AUC=10.82＋13.37c12 h is a good choice for AID outpatients after last-night dose. Bland-Altman analysis reveals that both the two models could effectively predict MPA AUC in Chinese adult AID patients receiving MMF concomitant methylprednisolone therapy.

关 键 词：有限取样法 霉酚酸 自身免疫性疾病 药动学 

分 类 号：R969.4[医药卫生—药理学]