肾移植患者应用微乳化环孢素后监测血药谷浓度、峰浓度的临床价值比较

Comparison of clinical value in monitoring blood concentration trough level and peak level of micro emulsion ciclosporin for renal transplant recipients

目的对应用微乳化环孢素（又称新山地明,sandimmun neoral）的肾移植患者进行血药浓度监测,比较监测血药谷浓度（C0）和峰浓度（C2）的临床价值。方法对122例接受同种尸体肾移植的患者术后随机分为Ⅰ组（62例）和Ⅱ组（60例）,两组均采用微乳化环孢素＋麦考酚吗乙酯（MMF）＋肾上腺皮质激素三联免疫抑制剂方案。两组分别以C2、C0作为微乳化环孢素血药浓度监测及调整剂量的指标。Ⅰ组微乳化环孢素的C2目标浓度：3个月内为1200~1400ng/ml,3~6个月为900~1200ng/ml。Ⅱ组微乳化环孢素的C0目标浓度：3个月内为250~350ng/ml,3~6个月为200~250ng/ml。比较两组移植术后3个月内（术后1周、2周、4周、12周4个时点）微乳化环孢素C0、C2值,并与血药浓度-时间曲线下面积（area under the plasma concentration-time curve,AUC）0~12进行直线相关分析。比较急性排斥反应（AR）与非AR患者的C0、C2值及AUC0~12。记录微乳化环孢素相关肝、肾毒性反应时血药C0、C2值,并与AUC0~12进行直线相关分析。结果所有患者均得到随访,平均随访时间12.7个月。肾移植术后3个月内微乳化环孢素C0值与AUC0~12无相关（r=0.41,P〉0.05）,C2值与AUC0~12呈正相关（r=0.87,P〈0.05）。Ⅱ组AR发生率明显高于Ⅰ组（28%比7%,P〈0.05）。AR患者的微乳化环孢素C0平均值在目标浓度范围内,但C2值明显低于非AR患者,且AR患者的AUC0~12明显低于非AR患者（P〈0.05~P〈0.01）。微乳化环孢素的C0、C2值和AUC0~12与该药相关的肝、肾毒性反应无关。结论对于肾移植术后早期微乳化环孢素的血药浓度监测,C0值并不能精确地反映该药的血药浓度;C2值与AUC0~12具有较好的相关性,C2值对预测排斥反应及肾移植患者的免疫抑制是否足够更为敏感。

Objective To monitor the blood concentration of micro emulsion ciclosporin（sandimmun neoral）in renal transplant recipients and compare the clinical value between blood concentration trough level（C0）and peak level（C2）.Methods One hundred and twenty-two cadaveric renal transplant recipients were randomly divided into group Ⅰ（n=62）and group Ⅱ（n=60）.All patients were treated with micro emulsion ciclosporin,mycophenolate mofetil（MMF）and adrenal cortex hormone.C0 and C2 in two groups were chosen as indices to monitor the blood concentration and adjust dosage.The target levels C2 of Sandimmun neoral in groupⅠ were 1 200-1 400 ng/ml during the first 3 months after transplantation and 900-1 200 ng/ml from 3 to 6 months after transplantation.The target levels C0 of Sandimmun neoral in groupⅡ were 250-350 ng/ml in the first 3 months after transplantation and 200-250 ng/ml from 3 to 6 months after transplantation.The C0 and C2 values of two groups were compared in 3 months after transplantation（4 different time points of week 1,week 2,week 4,week 12 after transplantation）.The linear correlation analysis was taken in C0,C2 values and area under the plasma concentration-time curve（AUC）0-12.The C0,C2 values and AUC0-12 were compared in acute rejection（AR）cases and no AR cases.The C0,C2 values of micro emulsion ciclosporin were recorded when the drug＇s related hepatotoxicity and nephrotoxicity occurred.And the linear correlation analysis was taken in C0,C2 values and AUC0-12.Results All patients were followed up（mean 12.7 months）.There was no significant correlation between C0 values and AUC0-12 in 3 months after renal transplantation（r=0.41,P0.05）.And there was significantly positive correlation between C2 values and AUC0-12（r=0.87,P0.05）.The incidence of AR in groupⅡ was higher than that in groupⅠ（28 % vs.7 %,P0.05）.The average values of micro emulsion ciclosporin C0 in AR patients were within the target range.But C2 values and AUC0-12 of AR patients were significantly lower than that of patients without AR（P0.05-P0.01）.The C0,C2 values and AUC0-12 had no correlation with micro emulsion ciclosporin related hepatotoxicity and nephrotoxicity.Conclusions C0 value is not a good parameter for monitoring the blood concentration of micro emulsion ciclosporin after renal transplantation.There is significant positive correlation between C2 value and AUC0-12.C2 value is more sensitive to predict rejection and immunosuppression after renal transplantation.