老年肾移植患者霉酚酸的药物代谢动力学特征及其临床意义  

Pharmacokinetics of mycophenolic acid in senile kidney transplant recipients and the clinical implications

作　　者：孟凡航[1] 王长希[1] 陈立中[1] 任斌[2] 黎曙霞[2] 费继光[1] 邓素雄[1] 邱江[1] 李军[1] 陈国栋[1] 

机构地区：[1]中山大学附属第一医院肾移植科,广州510080 [2]中山大学附属第一医院药学部实验室,广州510080

出　　处：《肾脏病与透析肾移植杂志》2007年第5期421-425,446,共6页Chinese Journal of Nephrology,Dialysis & Transplantation

摘　　要：目的:探讨60岁以上老年肾移植患者霉酚酸(MPA)药物代谢动力学特征,探索适合的治疗窗及有限采样法预测MPA血药浓度-时间曲线下面积(MPA-AUC0-12)的模型。方法:24例60岁以上老年肾移植患者(男17例,女7例),24例成年肾移植患者作为对照组(男15例,女9例)。在术后2～3个月时,清晨服用霉酚酸酯(MMF)前以及服药后0.5、1、1.5、2、3、4、6、8、10、12h取外周静脉血2ml,采用高效液相色谱法测定MPA浓度,计算平均谷浓度(C0)、峰浓度(Cmax)、平均达峰时间(Tmax),及MPA-AUC0-12,采用多重逐步回归法推导有限采样法计算简化MPA-AUC的模型,预测值和实测值的一致性评价采用Lewis方法。结果:随访至术后半年,两组患者均没有发生急性排斥反应,老年组发生肺部感染和(或)白细胞减少等严重不良反应(SAE)5例,成年组发生肺部感染合并白细胞减少1例;服用1.0g/d霉酚酸酯,两组患者的C0、Cmax、Tmax的差异没有统计学意义,但是老年组患者的MPA-AUC0-12明显低于成年组患者[(22.21±9.01)μg.h/mlvs(32.82±8.75)μg.h/ml,P<0.05];20.8%的老年患者出现早期双峰(服药后2～4h);老年组中发生SAE亚组的AUC0-12明显高于无SAE亚组(P<0.05),以25μg.h/ml为界分组,则高AUC0-12亚组的SAE发生率明显高于低AUC亚组(P<0.05);具有最佳预测效果的最小的有限采样法计算简化AUC的模型:AUC=3.0410+9.8588×C0+0.5963×C0.5+2.5612×C3(r2=0.893)。平均预测误差me及其95%的置信区间(95%CI)为0.17(-2.25,2.59),均方根预测误差rmse及其95%置信区间为3.85(0.70,5.49)。结论:服用同等剂量的MMF,老年肾移植患者的MPA-AUC0-12明显低于成年患者;治疗性药物浓度监测对于改善老年肾移植患者的预后具有肯定的意义,有限采样法计算简化AUC是实现MPA的治疗性药物浓度监测的有效、可行的手段。将MPA-AUC0-12控制在25μg.h/ml以下可有效降低SAE的发生率;使急性排斥反应风险升高的下限值仍需进一步研究Objective ：To investigate the pharmacokinetic characteristics of mycophenolic acid （ MPA）, and to explore a preliminary therapeutic window and a limited sampling strategy （LSS） for calculating the abbreviated MPA area under the curve （AUC0-12） in Chinese senile kidney transplant recipients. Methodology ：Twenty-four （17 male and 7 female） patients over 60-year old （65.6 ＋3.6） were enrolled as senile group （Gs） and 24 （ 15 male and 9 female） patients of （39. 6 ± 14. 3） years old as adult group （Ga）. The venous blood samples were taken at 0 （pre-dose） , 0. 5, 1, 1.5, 2, 3, 4, 6, 8, 10 and 12 hours after the morning dose of MMF in 10 to 12 weeks post-transplant. The plasma MPA concentrations were measured by a validated high-performance liquid chromatography method. The full AUC0-12 was calculated by means of linear trapezoidal rule when peak times （ Tamx ） and peak concentrations （ Cmax） were determined through observation. Multiple stepwise regression analysis was applied to define the appropriate time points for LSS and to deduce model equation that best estimate MPA-AUC. Lewis＇method was used to evaluate the agreement between estimated values and actual values. Results：In the follow-up period （6 month post-transplant） , there was no acut rejection （AR） episode when 5 senile and 1 adult experienced severe adverse events （SAE） such as pneumonia and leukocytopenia. The pharmacokinetic characteristics in the adult group were similar to the Asian population described in other report, but there were major differences in the senile group. When given the same dose of MMF （ 1.0 g/d） , MPA-AUC0-12 in Gs is significantly lower than that of Ga [ （ 22.21 ± 9.01 ） μg· h/ml vs （ 32. 82 ± 8. 75 ） μg· h/ml, P 〈 0. 05 ] , while no significant differences were found in Co, C0, and Tmax （ P 〉 0. 05 ）. The concentration-time curve of Gs displayed a bi-peak pattern in five patients （20. 8% ） during the early stage （2-4 hours post-dos

关 键 词：肾移植 老年 霉酚酸 药物代谢动力学 临床意义 

分 类 号：R699[医药卫生—泌尿科学]