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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 pharmacokinetics of mycophenolic acid (MPA) in elderly patients over 60 years of age with renal transplantation and to explore a suitable therapeutic window and limited sampling method to predict the MPA-AUC0-12 area under MPA . Methods: Twenty-four elderly renal transplant recipients aged 60 years and older (17 males and 7 females) and 24 adult kidney transplant recipients served as control group (15 males and 9 females). 2 to 3 months after surgery, before taking mycophenolate mofetil (MMF) and taking 0.5,1,1.5,2,3,4,6,8,10,12 h after taking peripheral blood 2ml, with high efficiency The concentration of MPA was determined by liquid chromatography and the average trough concentration (C0), peak concentration (Cmax), average peak time (Tmax), and MPA-AUC0-12 were calculated and calculated by the simplified multiple stepwise regression method. AUC model, the predictive value and the consistency of the measured value using the Lewis method. Results: During the follow-up period of six months after operation, no acute rejection occurred in both groups, 5 cases of severe adverse reactions (SAE) such as pulmonary infection and / or leucopenia occurred in the elderly group and 5 cases of lung infection and leukopenia in the adult group For example, taking 1.0g / d mycophenolate mofetil, there was no significant difference in C0, Cmax and Tmax between the two groups, but MPA-AUC0-12 in the elderly group was significantly lower than that in the adult group [(22.21 ± 9.01) (32.82 ± 8.75) μg.h / ml, P <0.05]; early peak appeared in 20.8% of elderly patients (2 ~ 4 h after taking the drug); AUC0-12 of SAE subgroup in the elderly group was significantly (P <0.05). The incidence of SAE in high AUC0-12 subgroup was significantly higher than that in low AUC subgroup (P <0.05), with the best prediction A Minimal Finite Sampling Method for Calculating the Simplified AUC Model: AUC = 3.0410 + 9.8588 × C0 + 0.5963 × C0.5 + 2.5612 × C3 (r2 = 0.893). Mean prediction error me and its 95% confidence interval (95% CI) were 0.17 (-2.25, 2.59). Root mean square prediction error rmse and its 95% confidence interval were 3.85 (0.70, 5.49). CONCLUSIONS: MPA-AUC0-12 in elderly patients with renal transplant recipients is significantly lower than that of adult patients with the same dose of MMF. The monitoring of therapeutic drug concentration has certain significance for improving the prognosis of elderly patients with renal transplantation. Finite sampling method to calculate the simplified AUC is achieved MPA therapeutic drug concentration monitoring effective and feasible means. The control of MPA-AUC0-12 at 25μg.h / ml or less can effectively reduce the incidence of SAE; make the lower limit of acute rejection risk needs further study.