Clinically useful limited sampling strategy to estimate area under the concentration-time curve of once-daily tacrolimus in adult Japanese kidney transplant recipients

BackgroundAn extended-release, once-daily, oral formulation of tacrolimus is currently used after kidney transplantation as a substitute for the conventional twice-daily formulation. The purpose of this study was to provide a limited sampling strategy with minimum and optimum sampling points to predict the tacrolimus area under the concentration-time curve (AUC) after administration of once-daily tacrolimus in de novo adult kidney transplant patients.MethodsA total of 36 adult Japanese kidney transplant patients receiving once-daily tacrolimus were included: 31 were allocated to a study group to develop limited sampling strategy (LSS) model equations based on multiple stepwise linear regression analysis, and 5 were allocated to a validation group to estimate the precision of the LSS equations developed by the study group. Twelve-hour AUC (AUC0-12) was calculated by the trapezoidal rule, and the relationship between individual concentration points and AUC0-12 were determined by multiple linear regression analysis. The coefficient of determination (R2) was used to assess the goodness-of-fit of the regression models. Three error indices (mean error, mean absolute error, and root mean squared prediction error) were calculated to evaluate predictive bias, accuracy, and precision, respectively. Quality of the statistical models was compared with Akaike's information criterion (AIC).ResultsA four-point model using C0, C2, C4 and C6 gave the best fit to predict AUC0-12 (R2 = 0.978). In the three- and two-point models, the best fits were at time points C2, C4, and C6 (R2 = 0.973), and C2 and C6 (R2 = 0.962), respectively. All three models reliably estimated tacrolimus AUC0-12, consistent with evaluations by the three error indices and Akaike’s information criterion. Practically, the two-point model with C2 and C6 was considered to be the best combination, providing a highly accurate prediction and the lowest blood sampling frequency.ConclusionsThe two-point model with C2 and C6 may be valuable in reducing the burden on patients, as well as medical costs, for once-daily tacrolimus monitoring.背景：目前，他克莫司（tacrolimus）的每日一次口服缓释制剂已被应用于肾移植术后，以替代传统的每日两次给药制剂。本研究旨在构建一种采样点最少且最优的有限采样策略，用于预测初治成年肾移植患者服用每日一次他克莫司后的浓度-时间曲线下面积（area under the concentration-time curve, AUC）。 方法：本研究共纳入36例接受每日一次他克莫司治疗的日本成年肾移植患者：其中31例被分配至研究组，基于多重逐步线性回归分析构建有限采样策略（limited sampling strategy, LSS）模型方程；剩余5例被分配至验证组，用于评估研究组所构建的LSS模型方程的精密度。采用梯形法计算12小时浓度-时间曲线下面积（AUC0-12），并通过多重线性回归分析明确个体采血浓度点与AUC0-12之间的关联。以决定系数（R²）评估回归模型的拟合优度。分别计算三项误差指标——平均误差（mean error）、平均绝对误差（mean absolute error）与均方根预测误差（root mean squared prediction error），以分别评估模型的预测偏倚、准确度与精密度。采用赤池信息准则（Akaike's information criterion, AIC）比较各统计模型的质量。 结果：采用C0、C2、C4与C6的四点模型对AUC0-12的预测拟合效果最佳（R²=0.978）。三点模型与两点模型的最优采样时间点分别为C2、C4、C6（R²=0.973）与C2、C6（R²=0.962）。经三项误差指标与赤池信息准则评估，上述三种模型均可可靠预测他克莫司AUC0-12。实际应用中，采用C2与C6的两点模型被认为是最优组合，其预测准确度高且采血频次最低。 结论：采用C2与C6的两点模型可有效降低每日一次他克莫司治疗监测过程中的患者负担与医疗成本，具有较高的临床应用价值。