摘要
目的建立有限采样策略估算。肾移植受者霉酚酸钠药.时曲线下面积(AUC)的公式。方法2010--2013年南京军区福州总医院接受霉酚酸钠肠溶片(EC-MPS)联合钙调磷酸蛋白酶抑制剂(CNI)及泼尼松三联免疫抑制治疗的35例肾移植受者,血霉酚酸浓度采用均相酶免疫分析(EMIT)法测定,测定时间点为服药前及服药后0.5、1.0、1.5、2.0、3.0、4.0、6.0、8.0、12.0h。采用WINNOLIN软件计算霉酚酸的药代动力学参数。多元逐步回归分析法得出适合中国人群服用不同CNI药物时的简化霉酚酸药-时AUC计算公式。结果35例受者霉酚酸的AUC0-12b为14~67mg·h/L,平均(37±14)mg·h/L;不同肾移植受者之间药代动力学参数个体差异大,霉酚酸的谷浓度(C0)与霉酚酸的AUC0-12b相关性差(r2=0.090)。服用他克莫司的受者采用4个时间点取样的霉酚酸浓度(C4、C6、C8、C12)得出霉酚酸的AUC简化计算公式为AUC=5.678+1.718×C4+2.853×C6+1.812XC8+3.413×C12;该公式的霉酚酸AUC预测值与AUC0-12h实测值相关性较好(r2=0.890,P〈0.05),绝对预测误差中位数为3.45%(0.41%~24.71%),误差超过15%的比例为11.1%(2/18)。服用环孢素A的患者采用4个时间点取样的霉酚酸浓度(C3、C4、C6、C7)得出霉酚酸AUC简化计算公式为AUC=7.072+1.525XC3+1.558×C4+1.573XC6+2.285×CE;该公式的霉酚酸AUC预测值与AUC0-12h实测值相关性好(r2=0.952,P〈0.05),绝对预测误差中位数为6.50%(0.02%-12.91%),误差超过15%的比例为0。上述两个公式经Bland-Altman分析,与霉酚酸AUC0-12h一致性良好。结论本研究拟合的4点霉酚酸AUC简化计算公式能较好地反映霉酚酸药.时AUC,适用于肾移植受者服用EC—MPS的治疗药物监测。
Objective To establish a formula for estimating area under the concentration-versus- time curve (AUC) of mycophenolate sodium in Chinese renal allograft recipients with a limited sampling model. Methods A total of 35 renal allograft recipients were recruited from 2010 to 2013 to receive enteric- coated mycophenolate sodium ( EC-MPS), calcineurin (CNI) and prednisone as immunosuppressive triple therapy. The serum concentration of mycophenolic acid (MPA) was assayed by enzyme multiplied immunoassay technique (EMIT) at pre-dose ( Co ), 0. 5 ( C0.5 ), 1.0 ( C1 ), 1.5 ( C1.5 ), 2. 0 ( C2 ), 3.0 (C3 ), 4. 0 ( C4 ), 6.0 ( C6 ), 8.0 ( Cs ) and 12.0 ( C,2 ) h post-dose respectively. Pharmacokinetic parameters of MPA ( Co, CI2, Cm~, T AUC0-12 h) were calculated by software WINNOLIN. Simplified formulae for estimation of MPA-AUC in tacrolimus ( Tac ) group or cyclosporin A ( CsA ) group were established by multiple stepwise regression analysis. Results There were variable MPA AUC0_12 h levels between 14 and 67 mg h/L (mean: 37 + 14). The MPA trough level (Co) had no correlations with MPA AUC0-12h(r2 =0. 090). The simplified MPA AUC formula for Tac group was AUC = 5. 678 + 1. 718 x C4 +2. 853 x C6 + 1. 812 x Cs + 3. 413 x CIz with four sampling points ( C4, C6 , C8 , C12 ). Estimated AUC with the formula had eorrelations with AUC0_lz h ( r2 = 0. 890 ). The mean absolute prediet error (APE) was 3.45% (0. 41% -24. 71% ) and the proportion of APE above 15% stood at 11.1% (2/18). In CsA group, the simplified MPA AUC formula was AUC = 7. 072 + 1. 525 C3 + 1. 558 x C4 + 1. 573 x C6 + 2. 285 x C8. The correlation was r2 =0. 952, mean APE was 6. 50% (0.02% - 12. 91% ) and proportion of APE above 15% stood at 0. The above formulae were observed to have agreement with AUC0-12h by Bland-Ahman analysis. Conelusion The simplified MPA AUC formulae with 4-point sampling provide an effective approach for estimating full MPA AUC0-12h in Chinese renal recipients on EC-MPS plus tacrolimus or cyclosporin A.
出处
《中华医学杂志》
CAS
CSCD
北大核心
2013年第48期3841-3846,共6页
National Medical Journal of China
基金
卫生部国际交流与合作中心合作项目(IHECC08-201216)
关键词
肾移植
霉酚酸
药代动力学
药物监测
有限采样法
Kidney transplantation
Mycophenolic acid
Pharmacokinetics
Drug monitoring
Limited sampling strategy