Division of Nephrology, Department of Medicine, Leiden University Medical Center, Leiden, The Netherlands.
Leiden Transplant Center, Leiden University Medical Center, Leiden, The Netherlands.
Clin Pharmacol Ther. 2023 Jul;114(1):192-200. doi: 10.1002/cpt.2915. Epub 2023 May 10.
Evidence to define target ranges for tacrolimus (Tac) and mycophenolic acid (MPA) exposure after the first year of kidney transplantation is limited. We investigated the association of measurements at 1 year and repeated measurements of real-world Tac-trough levels (C ) and abbreviated area under the curve from zero to 12 hours (AUC ) of Tac and MPA with biopsy-proven acute rejection (BPAR) between years 1 and 3 post-transplant in 968 kidney transplant recipients (KTRs). Thirty-five (3.6%) out of 968 KTRs experienced BPAR. Both Tac-AUC (hazard ratio (HR): 0.39, 95% confidence interval (CI): 0.30-0.50, P < 0.001), Tac-C (HR: 0.46, 95% CI: 0.38-0.57, P < 0.001) and MPA-AUC at 1 year (HR: 0.80, 95% CI: 0.68-0.94, P = 0.006), as well as repeated measurements of Tac-C (HR: 0.70, 95% credibility interval (CrI): 0.61-0.82, P < 0.001), and of MPA-AUC (HR: 0.75, 95% CrI: 0.62-0.93, P < 0.001) were associated with BPAR. In our population, the recommended target range for Tac-AUC at 1 year would be 75-95 nghour/mL and a Tac-C 5-7 ng/mL. The Tac-AUC predicted BPAR better than Tac-C and identified KTRs with over- or underexposure despite supposedly adequate Tac-C . We did not find evidence to recommend another target than the consensus range of 30-60 mghour/L for MPA-AUC after the first year of transplantation. To our knowledge, this is a first study on the simultaneous exposure of Tac and MPA at year 1 and subsequent BPAR up to year 3, which may help define the therapeutic target window for the longer term.
在肾移植后的第一年，用于定义他克莫司（Tac）和霉酚酸（MPA）暴露目标范围的证据有限。我们调查了 968 例肾移植受者（KTR）中，1 年时的测量值以及 Tac 实际谷浓度（C）和零至 12 小时时的 Tac 和 MPA 曲线下面积（AUC）的重复测量值与移植后 1 至 3 年期间活检证实的急性排斥反应（BPAR）之间的相关性。968 例 KTR 中有 35 例（3.6%）发生 BPAR。Tac-AUC（风险比（HR）：0.39，95%置信区间（CI）：0.30-0.50，P<0.001）、Tac-C（HR：0.46，95%CI：0.38-0.57，P<0.001）和 MPA-AUC 在 1 年时（HR：0.80，95%CI：0.68-0.94，P=0.006）以及 Tac-C 的重复测量值（HR：0.70，95%可信度区间（CrI）：0.61-0.82，P<0.001）和 MPA-AUC（HR：0.75，95%CrI：0.62-0.93，P<0.001）与 BPAR 相关。在我们的人群中，1 年时 Tac-AUC 的推荐目标范围为 75-95nghour/mL，Tac-C 为 5-7ng/mL。Tac-AUC 预测 BPAR 的效果优于 Tac-C，并且尽管 Tac-C 被认为是足够的，但它可以识别出 Tac 暴露过度或不足的 KTR。我们没有发现证据表明，在移植后的第一年之后，除了共识范围 30-60mghour/L 之外，还需要推荐另一个 MPA-AUC 目标。据我们所知，这是第一项关于 Tac 和 MPA 在第 1 年的同时暴露以及随后在第 3 年发生的 BPAR 的研究，这可能有助于确定更长时间的治疗目标范围。
