与成人相比，儿童肾移植受者体内环孢素 A 的敏感性增加。
Increased cyclosporin a sensitivity in vivo in pediatric renal transplant recipients compared with adults.
机构信息
Department of Pediatrics I, University Children's Hospital, Heidelberg, Germany.
出版信息
Ther Drug Monit. 2012 Oct;34(5):554-60. doi: 10.1097/FTD.0b013e3182697655.
BACKGROUND
Developmental regulation of the pharmacodynamics of cyclosporin A (CsA) has been suggested by in vitro studies. However, these results have not yet been reproduced in the complexity of an in vivo immune system, because reliable biomarkers of CsA effects have not been available.
METHODS
Gene expression of interleukin-2 (IL-2), interferon (IFN)-γ, and granulocyte macrophage colony stimulating factor (GM-CSF) in peripheral blood from stable pediatric (N = 31) and adult renal transplant recipients (N = 153) (age range 6.5-78 years) was measured by quantitative real-time polymerase chain reaction before (C0) and 2 hours (C2) after oral CsA intake. To control for the effect of varying CsA concentrations, an index was calculated as a measure of individual CsA sensitivity.
RESULTS
The CsA sensitivity of IL-2 gene expression in pediatric patients was 3.9% higher than in middle-aged adults and 5.2% higher than in seniors, indicating stronger immunosuppression at a given CsA blood concentration in younger patients. For the entire patient cohort, there was a statistically significant inverse correlation between the CsA sensitivity of IL-2 and chronological age (r = 0.142, P < 0.0001). Also, the CsA sensitivity of IFN-γ (r = 0.131, P < 0.0001) and GM-CSF (r = 0.036, P < 0.01) were inversely correlated with chronological age. Multiple linear regression analysis revealed that age was a highly significant (P = 0.0027) independent predictor for residual gene expression of IL-2, but not of IFN-γ and GM-CSF.
CONCLUSIONS
An increased sensitivity of IL-2 to suppression by CsA was found in pediatric renal transplant recipients in vivo compared with adults. Hence, there seems to be an effect of human development on CsA pharmacodynamics, which, besides the effect of age on pharmacokinetics, should also be considered for the design of treatment regimens of CsA and potentially other calcineurin inhibitors in the pediatric patient population.
背景
体外研究表明，环孢素 A（CsA）的药效学具有发育调节作用。然而，由于缺乏可靠的 CsA 作用生物标志物，这些结果尚未在复杂的体内免疫系统中重现。
方法
通过定量实时聚合酶链反应，检测了 31 名稳定期儿科（年龄 6.5-78 岁）和 153 名成年肾移植受者（年龄 6.5-78 岁）外周血白细胞介素-2（IL-2）、干扰素（IFN）-γ和粒细胞-巨噬细胞集落刺激因子（GM-CSF）的基因表达，在口服 CsA 摄入前（C0）和 2 小时（C2）后进行测量。为了控制 CsA 浓度变化的影响，计算了一个指数作为个体 CsA 敏感性的衡量标准。
结果
儿科患者 IL-2 基因表达的 CsA 敏感性比中年成人高 3.9%，比老年人高 5.2%，表明在给定的 CsA 血药浓度下，年轻患者的免疫抑制作用更强。对于整个患者队列，IL-2 的 CsA 敏感性与年龄呈统计学显著负相关（r = 0.142，P < 0.0001）。此外，IFN-γ（r = 0.131，P < 0.0001）和 GM-CSF（r = 0.036，P < 0.01）的 CsA 敏感性与年龄呈负相关。多元线性回归分析显示，年龄是 IL-2 残留基因表达的高度显著（P = 0.0027）独立预测因子，但不是 IFN-γ和 GM-CSF 的独立预测因子。
结论
与成人相比，体内儿科肾移植受者的 IL-2 对 CsA 的抑制作用更为敏感。因此，人类发育对 CsA 药效学有影响，除了年龄对药代动力学的影响外，在设计 CsA 和潜在的其他钙调神经磷酸酶抑制剂在儿科患者人群中的治疗方案时，还应考虑这一影响。
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