他克莫司血药浓度-时间曲线下面积监测方法

目的 探讨肾移植术后准确反映他克莫司(FK506)药物浓度-时间曲线下面积(AUC)的监测方法.方法 16例肾移植受者先用抗淋巴细胞球蛋白和甲泼尼龙诱导治疗3 d,术后第3天首剂口服0.075 mg/kg FK506后,以ELISA法测定服药后各时间点血药浓度,采用3p87药代动力学计算程序将测得的FKS06浓度自动拟合计算出各药代动力学参数,利用Pearson相关和多元线性逐步引入--剔出回归(Stepwise)等统计学方法,统计处理FKS06各时间点血药浓度与AUC之间的相关性数据,计算出相关系数(r)、回归方程和多元相关系数(R).结果 首剂口服同一剂量FK506后,除C1.0外,C0.5、C1.5、C2.0、C3.0、C5.0、C8.0、C12.0与AUC之间的相关性差异有统计学意义(均P＜0.05).多元回归方程显示单时间点血药浓度C15与AUC相关性最好(R=0.92,R2=0.85),若应用两时间点血药浓度及三时间点血药浓度的简化的AUC监测策略,C2.0、C1.5及C5.0、C1.5、C3.0与AUC的相关性最好(R=0.97,R2=0.94及R=0.99,R2=0.99).结论 首剂口服同一剂量FK506后,C5.0监测方法可能是最准确的单时间点血药浓度的AUC监测;C5.0、C1.5或者C5.0、C1.5、C3.0简约AUC监测方法可能是最具成本-疗效的FK506临床监测策略.

Clinical monitoring method of area under the concentrations-time curve after the first oral tacrolimus

Objective To assess the predictability of individual tacrolimus (FK506) concentrations at different time points for the area under the curve (AUC) and to find the best sampling time for the abbreviated AUC to predict the total body exposure of tacrolimus. Methods 16 primary kidney transplant recipients were treated with methylprednisolone and antilymphocyte globulin for 3 days. The first tacrolimus oral dose, 0.075 mg/kg, was given at day 3 after transplantation. Blood samples were obtained at 0.5,1.0, 1.5, 2.0, 3.0, 5.0, 8.0, and 12.0 hours since taking the first oral dose. The tacrolimus blood concentration was measured by ELISA. Twelve-hour AUC (AUC12) for each patient was calculated using linear trapezoid rule. Associations between blood concentration at each sampling time points and the AUC12were measured by Pearson correlation coefficients. Abbreviated sampling equations were derived by multiple,stepwise regression analyses performed using AUC12 as the dependent variables. The variance in the strength of association between predicted AUC (AUCp) and AUC12 was reflected by the linear regression coefficient the minimum AUC12. The correlation between all the time points concentration, except C1.0, all the drug concentrations at different time points were significantly correlated with AUC ( all P＜0.05 ). Stepwise multiple regression showed that C5.0 might be the best predictor of the total body exposure of tacrolimus (R=0.92, R2=0.85). According to an abbreviated AUC monitoring strategy, the concentrations at hours 5 and 1.5 or hours 5, 1.5, and 3 were well correlated with AUC (R=0.97, R2=0.94 and R=0.99, R2=0.99, respectively). Conclusion Tacrolimus AUC12 shows remarkable interindividual variation after the first oral dose in Chinese renal transplant recipients. C5 may be the best predictor of the first AUC12. Twopoint sampling method using C5 and C1.5 and the three-point sampling method using C5, C1.5, and C3 may be the best abbreviated AUC to cost-effective tacrolimus monitoring strategy.