Shihab Fuad, Christians Uwe, Smith Lonnie, Wellen Jason R, Kaplan Bruce
University of Utah School of Medicine, Salt Lake City, UT, USA.
University of Colorado Denver, Aurora, CO, USA.
Transpl Immunol. 2014 Jun;31(1):22-32. doi: 10.1016/j.trim.2014.05.002. Epub 2014 May 24.
Mammalian target of rapamycin (mTOR)-inhibitor-containing immunosuppressive regimens have been developed as part of calcineurin inhibitor (CNI) minimization/withdrawal strategies for renal transplant recipients, with the goal of avoiding CNI-associated nephrotoxicity. This review focuses on the pharmacokinetic interactions and exposure-response relationships of mTOR inhibitors and tacrolimus (TAC), the most widely used CNI. We also discuss key randomized clinical studies that have evaluated use of this combination in renal transplantation. Pharmacokinetic studies have shown that mTOR inhibitors, everolimus (EVR) and sirolimus (SRL), have a large intra- and inter-patient variability in drug exposure, and narrow therapeutic windows (trough levels [C0] 3-8 ng/mL and 5-15 ng/mL, respectively). Consequently, routine therapeutic drug monitoring of EVR and SRL is recommended to optimize efficacy and minimize toxicity in individual patients. As there is a good correlation between C0 and area under the curve (AUC), C0 can be used as a convenient and reliable measure of mTOR drug exposure. Clinical data on the use of EVR or SRL in TAC minimization strategies in renal transplantation are limited. Available evidence suggests that treatment with EVR allows early and substantial TAC minimization when used with basiliximab induction and corticosteroids, to achieve good renal function without compromising efficacy or safety. However, data comparing this combination with other regimens are lacking. Results with SRL are more mixed. SRL in combination with reduced TAC has been shown to provide less nephrotoxicity than the SRL/standard TAC combination, with comparable efficacy and safety. However, this approach has been shown to be inferior to other regimens in terms of patient/graft survival and biopsy-proven acute rejection (vs MMF/TAC) as well as renal function (vs MMF/TAC and SRL/MMF). Further studies are needed to define the therapeutic window for TAC when used in combination with mTOR inhibitors, evaluate EVR/reduced TAC versus other regimens, assess long-term outcomes, and determine efficacy and safety in high-risk patients.
含雷帕霉素哺乳动物靶点（mTOR）抑制剂的免疫抑制方案已被开发出来，作为肾移植受者钙调神经磷酸酶抑制剂（CNI）最小化/撤药策略的一部分，目的是避免与CNI相关的肾毒性。本综述重点关注mTOR抑制剂与使用最广泛的CNI他克莫司（TAC）的药代动力学相互作用和暴露-反应关系。我们还讨论了评估该联合用药在肾移植中应用的关键随机临床研究。药代动力学研究表明，mTOR抑制剂依维莫司（EVR）和西罗莫司（SRL）在患者内和患者间的药物暴露存在很大差异，且治疗窗较窄（谷浓度[C0]分别为3 - 8 ng/mL和5 - 15 ng/mL）。因此，建议对EVR和SRL进行常规治疗药物监测，以优化个体患者的疗效并将毒性降至最低。由于C0与曲线下面积（AUC）之间具有良好的相关性，C0可作为mTOR药物暴露的便捷可靠指标。关于EVR或SRL在肾移植TAC最小化策略中应用的临床数据有限。现有证据表明，与巴利昔单抗诱导和皮质类固醇联合使用时，EVR治疗可使TAC早期大幅减量，在不影响疗效或安全性的情况下实现良好的肾功能。然而，缺乏将该联合用药与其他方案进行比较的数据。SRL的结果则更为复杂。已表明SRL与减量TAC联合使用比SRL/标准TAC联合用药具有更低的肾毒性，疗效和安全性相当。然而，在患者/移植物存活以及活检证实的急性排斥反应（与霉酚酸酯/他克莫司相比）和肾功能（与霉酚酸酯/他克莫司和SRL/霉酚酸酯相比）方面，该方法已被证明不如其他方案。需要进一步研究来确定TAC与mTOR抑制剂联合使用时的治疗窗，评估EVR/减量TAC与其他方案的疗效，评估长期结局，并确定高危患者的疗效和安全性。
