Miura Masatomo, Satoh Shigeru, Niioka Takenori, Kagaya Hideaki, Saito Mitsuru, Hayakari Makoto, Habuchi Tomonori, Suzuki Toshio
Department of Pharmacy, Akita University Hospital, Akita, Japan.
Ther Drug Monit. 2008 Feb;30(1):52-9. doi: 10.1097/FTD.0b013e31815f5416.
The aim of this study was to develop a limited sampling strategy to allow the simultaneous estimation of the area under the concentration-time curves (AUCs) of tacrolimus and mycophenolic acid (MPA), the active metabolite of the prodrug mycophenolate mofetil, using a small number of samples from patients undergoing renal transplantation. Fifty Japanese patients were enrolled. On day 28 after transplantation, samples were collected just before and 1, 2, 3, 4, 6, 9, and 12 hours after tacrolimus and mycophenolate mofetil administration at 9:00 am and 9:00 pm. The full pharmacokinetic profiles obtained from these timed concentration data were used to choose the best sampling times. Three error indices (percent mean error, percent mean absolute error, and percent relative mean square error) were used to evaluate the predictive bias, accuracy, and precision. The predicted AUC0-12 of MPA calculated at the three time points of C2h-C4h-C9h best approximated the actual AUC0-12 of MPA (r = 0.877), and the AUC0-12 of tacrolimus calculated at the same time points predicted a good correlation with the actual AUC (r = 0.928). When the three sampling times of trough level (C0h) and two other points within 4 hours after administration were used, the three points of C0h-C2h-C4h were the best points for estimation of the AUC0-12 tacrolimus and MPA (AUC0-12 = 7.04.C0 + 1.71.C2 + 3.23.C4 + 15.19, r = 0.799, P < 0.001 and AUC0-12 = 0.26.C0 + 2.06.C2 + 3.82.C4 + 20.38, r = 0.693, P < 0.001, respectively). The percent mean error, percent mean absolute error, and percent relative mean square error of the prediction formula using the three time points of C0h-C2h-C4h were -0.3%, 8.8%, and 13.5% for tacrolimus and 2.9%, 17.1%, and 21.5% for MPA, respectively. A limited sampling strategy using C2h-C4h-C9h provides the most reliable and accurate simultaneous estimation of the AUC0-12 of tacrolimus and MPA in patients undergoing renal transplantation. In addition, a limited sampling strategy using C0h-C2h-C4h is recommended for the simultaneous estimation of the AUC0-12 of tacrolimus and MPA when focused on samples collected within 4 hours after administration for clinical expediency.
本研究的目的是制定一种有限采样策略，以便能够利用肾移植患者的少量样本，同时估算他克莫司以及前药霉酚酸酯的活性代谢产物霉酚酸（MPA）的浓度-时间曲线下面积（AUC）。招募了50名日本患者。在移植后第28天，于上午9:00和晚上9:00给予他克莫司和霉酚酸酯后，分别在给药前以及给药后1、2、3、4、6、9和12小时采集样本。从这些定时浓度数据获得的完整药代动力学曲线用于选择最佳采样时间。使用三个误差指标（平均误差百分比、平均绝对误差百分比和相对均方误差百分比）来评估预测偏差、准确性和精密度。在C2h - C4h - C9h这三个时间点计算得到的MPA的预测AUC0 - 12最接近MPA的实际AUC0 - 12（r = 0.877），并且在相同时间点计算得到的他克莫司的AUC0 - 12与实际AUC具有良好的相关性（r = 0.928）。当使用谷浓度水平（C0h）的三个采样时间点以及给药后4小时内的另外两个时间点时，C0h - C2h - C4h这三个点是估算他克莫司和MPA的AUC0 - 12的最佳点（AUC0 - 12 = 7.04·C0 + 1.71·C2 + 3.23·C4 + 15.19，r = 0.799，P < 0.001；以及AUC0 - 12 = 0.26·C0 + 2.06·C2 + 3.82·C4 + 20.38，r = 0.693，P < 0.001）。使用C0h - C2h - C4h这三个时间点的预测公式的平均误差百分比、平均绝对误差百分比和相对均方误差百分比，他克莫司分别为 - 0.3%、8.8%和13.5%，MPA分别为2.9%、17.1%和21.5%。使用C2h - C4h - C9h的有限采样策略能够为肾移植患者提供最可靠且准确的他克莫司和MPA的AUC0 - 12的同时估算。此外，当出于临床便利性考虑而专注于给药后4小时内采集的样本时，建议使用C0h - C2h - C4h的有限采样策略来同时估算他克莫司和MPA的AUC0 - 12。
