MTOR抑制剂的药效学监测

Pharmacodynamic Monitoring of mTOR Inhibitors.

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|核心内容：

药效学(PD)监测可作为mTOR抑制剂(MTORis)常规药代动力学监测的补充，以期更好地指导器官移植后西罗莫司(SRL)或维罗莫司(EVR)的个体化治疗。

本文重点介绍了PD生物标记物在个体化mTORi治疗中的应用现状。

不同的策略已经被用来评估SRL和EVR的药效学，作为它们对移植后免疫反应影响的替代。

这包括检测p70S6K(70 kDa核糖体蛋白S6激酶)活性、p70S6K磷酸化(P-p70S6K)或P-S6蛋白表达。

与Western blot和ELISA相比，流式细胞术可以检测磷酸化蛋白，并将激活诱导的细胞内信号分子的变化与同一样本中相同细胞的未受刺激群体区分开来。

或者，在接受联合治疗的患者中，另一种PD方法是考虑生物标记物，如钙调神经磷酸酶抑制剂的NFAT残留表达，或评估药物的非特异性效应，如淋巴细胞增殖、白细胞介素合成、特异性外周血T调节亚群或淋巴细胞表面抗原，这些都有利于反映所实现的整体免疫抑制状态。

虽然有限，但关于mTOR途径生物标记物的现有数据似乎是有希望的。在临床实施之前，分析方法必须标准化和交叉验证，选定的生物标记物必须证明其在多中心临床试验中用于SRL或EVR剂量个体化的临床实用性。

原文摘要：

Pharmacodynamic (PD) monitoring may complement routine pharmacokinetic monitoring of mTOR inhibitors (mTORis) in an attempt to better guide individualized sirolimus (SRL) or everolimus (EVR) treatment after organ transplantation. This review focuses on current knowledge about PD biomarkers for personalized mTORi therapies. Different strategies have already been used in the evaluation of the pharmacodynamics of SRL and EVR as a proxy for their effects on the immune response after transplantation. These include measuring p70S6K (70 kDa ribosomal protein S6 kinase) activity, p70S6K phosphorylation (P-p70S6K), or P-S6 protein expression. Compared with Western blot and ELISA, phosphoflow cytometry can detect phosphorylated proteins and differentiate activation-induced changes of signaling molecules inside the cell from unstimulated populations of identical cells in the same sample. Alternatively, in patients receiving a combined therapy, the other PD approach is to consider biomarkers such as NFAT residual expression for calcineurin inhibitors or to evaluate nonspecific effects of the drugs such as lymphocyte proliferation, interleukin synthesis, specific peripheral blood T regulatory subsets, or lymphocyte surface antigens, which have the advantage to reflect the overall immunosuppressive status achieved. Although limited, the available data on mTOR pathway biomarkers seem promising. Before clinical implementation, the analytical methodologies must be standardized and cross-validated, and the selected biomarkers will have to demonstrate their clinical utility for SRL or EVR dose individualization in multicenter clinical trials.

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参考文献：https://sci-hub.ren/10.1097/FTD.0000000000000616

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