Citterio F
Department of Surgery, Catholic University of the Sacred Heart, Rome, Italy.
Transplant Proc. 2004 Mar;36(2 Suppl):420S-425S. doi: 10.1016/j.transproceed.2004.01.054.
The argument for the therapeutic monitoring of cyclosporin A (TDM-CyA), to optimize efficacy and safety, has been discussed in the last 25 years and it is still debated. Although CyA has been for more than 20 years the mainstay of immunosuppression in organ transplantation, no consensus has yet been achieved on TDM-CyA. The first proposed use of CyA was at fixed doses, but this was soon abandoned, and the predose, trough C0 blood level concept was introduced as a tool for TDM-CyA; however, no correlation could ever be shown between the various proposed trough therapeutic windows and major clinical events. On the contrary, the TDM-CyA of full area-under-the-curve (AUC) 0-12 exposure, significantly correlated with acute rejection and renal toxicity. The use of Neoral demonstrated that the region of most variability in CyA pharmacokinetics and the greatest calcineurin inhibition were confined within the AUC0-4, introducing the concept of absorption profiling. A further simplification come from the demonstration that C2, the single blood concentration measurement 2 hours after Neoral administration, was a significant accurate predictor of AUC0-4. The TDM-CyA with C2 has now been clinically validated in kidney, liver, and heart transplant recipients. In the last 25 years of TDM-CyA, some concepts have become clear: inadequate CyA exposure is a key risk factor for acute rejection and may contribute to the development of chronic rejection; C0 predose monitoring does not accurately measure CyA exposure. Thus, C2 single sampling offers today an innovative, simple, and accurate alternative for the pharmacokinetic clinical monitoring of CyA.
在过去25年里，人们一直在讨论通过环孢素A治疗药物监测（TDM - CyA）来优化疗效和安全性，且这一话题仍存在争议。尽管环孢素A在器官移植免疫抑制中作为主要药物已应用了20多年，但对于TDM - CyA尚未达成共识。最初提议使用环孢素A时采用的是固定剂量，但很快就被摒弃了，随后引入了给药前谷浓度C0血药水平的概念作为TDM - CyA的工具；然而，各种提议的谷治疗窗与主要临床事件之间从未显示出相关性。相反，0 - 12小时曲线下面积（AUC）的全区域TDM - CyA与急性排斥反应和肾毒性显著相关。新山地明（Neoral）的使用表明，环孢素A药代动力学中变化最大的区域以及最大的钙调神经磷酸酶抑制作用都局限在AUC0 - 4范围内，由此引入了吸收图谱的概念。进一步的简化是通过证明在新山地明给药后2小时的单次血药浓度测量值C2是AUC0 - 4的一个重要准确预测指标。目前，采用C2的TDM - CyA已在肾、肝和心脏移植受者中得到临床验证。在TDM - CyA的过去25年里，一些概念已经明确：环孢素A暴露不足是急性排斥反应的关键危险因素，可能导致慢性排斥反应的发生；给药前C0监测不能准确测量环孢素A的暴露情况。因此，如今C2单次采样为环孢素A的药代动力学临床监测提供了一种创新、简单且准确的替代方法。
