Department of Clinical Chemistry, Cliniques universitaires Saint-Luc, Université catholique de Louvain, Brussels, Belgium; Louvain Center for Toxicology and Applied Pharmacology (LTAP), Institut de Recherche Expérimentale et Clinique (IREC), Université catholique de Louvain, Brussels, Belgium.
Department of Clinical Chemistry, Cliniques universitaires Saint-Luc, Université catholique de Louvain, Brussels, Belgium; Louvain Center for Toxicology and Applied Pharmacology (LTAP), Institut de Recherche Expérimentale et Clinique (IREC), Université catholique de Louvain, Brussels, Belgium.
Pharmacol Res. 2016 Sep;111:610-618. doi: 10.1016/j.phrs.2016.07.027. Epub 2016 Jul 25.
Immunosuppressive drugs (IS) used in solid organ transplantation are critical dose drugs with high intra- and inter-subject variability. Therefore, IS therapeutic drug monitoring (TDM), mainly as trough levels analysis, is a major support to patient management, mandatory to optimize clinical outcome. Even though transplant patients undoubtedly benefited by this pre-dose (C0) monitoring, the relationship between these C0 concentrations and the incidence of graft rejections remains hardly predictable. Identification and validation of additional biomarkers of efficacy are therefore very much needed. As the main IS effects are mediated through the inhibition of lymphocyte proliferation pathways, direct drug quantification within this target compartment would appear meaningful, providing hopefully more consistent information on drug efficacy. Due to the analytical performances improvement, these intracellular concentrations became accessible for comprehensive studies regarding clinical benefit of intracellular IS TDM after solid organ transplantation. Over the last ten years, number of studies investigated the potential relationship between IS blood and intracellular pharmacokinetics, genetic variability, and clinical efficacy after solid organ transplantation. A recent literature review suggests that calcineurin inhibitors (tacrolimus and cyclosporine) intracellular concentrations appear more closely related to drug efficacy than blood levels. This closer association has however not been described for the m-TOR inhibitors (sirolimus, everolimus) and the antimetabolite (mycophenolic acid). Additional larger and multicenter clinical trials are needed to confirm these observations.
免疫抑制药物（IS）在实体器官移植中是关键剂量药物，具有高度的个体内和个体间变异性。因此，IS 治疗药物监测（TDM），主要是作为谷浓度分析，是患者管理的主要支持，是优化临床结果的必要条件。尽管移植患者无疑受益于这种预剂量（C0）监测，但这些 C0 浓度与移植物排斥的发生率之间的关系仍然难以预测。因此，非常需要识别和验证额外的疗效生物标志物。由于 IS 的主要作用是通过抑制淋巴细胞增殖途径介导的，因此在该靶区室中直接进行药物定量似乎很有意义，有望提供更一致的药物疗效信息。由于分析性能的提高，这些细胞内浓度可以进行综合研究，以了解实体器官移植后细胞内 IS TDM 的临床获益。在过去的十年中，许多研究调查了 IS 血液和细胞内药代动力学、遗传变异与实体器官移植后临床疗效之间的潜在关系。最近的文献综述表明，钙调神经磷酸酶抑制剂（他克莫司和环孢素）的细胞内浓度与药物疗效比血液水平更密切相关。然而，这种更密切的关联尚未在 m-TOR 抑制剂（西罗莫司、依维莫司）和代谢物（霉酚酸）中描述。需要更多的大型多中心临床试验来证实这些观察结果。
