van Boekel G A J, Donders A R T, Hoogtanders K E J, Havenith T R A, Hilbrands L B, Aarnoutse R E
Department of Nephrology, Radboud university medical center, PO box 9101, 6500 HB, Nijmegen, The Netherlands,
Eur J Clin Pharmacol. 2015 Jul;71(7):811-6. doi: 10.1007/s00228-015-1863-6. Epub 2015 May 17.
The aim of this study was to develop a clinically applicable limited sampling strategy for ambulatory Caucasian kidney transplant patients to estimate area under the curve in a 24-h period (AUC0-24) of prolonged-release tacrolimus.
Twenty six kidney recipients, at least 6 months after transplantation, receiving prolonged-release tacrolimus, were enrolled. In each patient, seven blood samples were collected during a period of 24 h by use of the validated dried blood spot method. Best subset selection multiple linear regression was performed to derive limited sampling strategy (LSS). The equations were constrained to include a maximum of three samples collected within 4 h after the intake to maintain clinical applicability. To assess the predictive performance of LSS, residuals for each patient were calculated based on models fitted to a dataset where that patient was omitted.
The prediction formula for the AUC(0-24) using the time points 0, 2, and 4 h after ingestion (C(0h)-C(2h)-C(4h)) provided the highest correlation with the AUC(0-24) (r(2) = 0.95): AUC0-24 = 44.9 + 8.9 × C(0h) + 2.1 × C(2h) + 7.6 × C(4h). Measures for bias and precision, i.e., median percentage prediction error (MPPE) and median absolute prediction error (MAPE), were 0.4 and 4.8%, respectively. For the same patients, the correlation between C(24h) and AUC0-24 was worse (r(2) = 0.77) while MPPE and MAPE were 6.2 and 7.2%, respectively.
In the outpatient department, a LSS using C(0h)-C(2h)-C(4h) can be used for reliable estimation of the AUC(0-24) of prolonged-release tacrolimus.
本研究旨在为非卧床白种人肾移植患者制定一种临床适用的有限采样策略，以估算缓释他克莫司24小时内的曲线下面积（AUC0 - 24）。
纳入26例移植后至少6个月且接受缓释他克莫司治疗的肾移植受者。采用经验证的干血斑法，在每位患者24小时内采集7份血样。进行最佳子集选择多元线性回归以得出有限采样策略（LSS）。方程被限定为最多包含服药后4小时内采集的3份样本，以保持临床适用性。为评估LSS的预测性能，基于拟合排除该患者后的数据集模型，计算每位患者的残差。
使用服药后0、2和4小时的时间点（C(0h)-C(2h)-C(4h)）估算AUC(0 - 24)的预测公式与AUC(0 - 24)的相关性最高（r(2) = 0.95）：AUC0 - 24 = 44.9 + 8.9 × C(0h) + 2.1 × C(2h) + 7.6 × C(4h)。偏差和精密度的指标，即中位百分比预测误差（MPPE）和中位绝对预测误差（MAPE）分别为0.4%和4.8%。对于相同患者，C(24h)与AUC0 - 24之间的相关性较差（r(2) = 0.77），而MPPE和MAPE分别为6.2%和7.2%。
在门诊，使用C(0h)-C(2h)-C(4h) 的有限采样策略可用于可靠估算缓释他克莫司的AUC(0 - 24)。
