有限采样法估算中国肾移植受者霉酚酸体内暴露

Exposure Estimation of Mycophenolic Acid in Chinese Renal Transplant Recipients by Limited Sampling Strategy

目的:建立中国肾移植受者霉酚酸(MPA)有限采样法模型,预测采用不同免疫抑制方案的肾移植受者MPA的体内暴露。方法:首次肾移植术后早期受者108例,根据术后免疫抑制维持方案分为:环孢素(Cs A)+霉酚酸钠肠溶片(EC-MPS)组(n=49),他克莫司(TAC)+吗替麦考酚酯(MMF)组(n=32)以及TAC+EC-MPS组(n=27)。术后14 d在服药前(0 h)及服药后0.5,1,1.5,2,4,6,8,10,12 h采血,应用液相串联质谱法(LC-MS/MS)测定MPA血浆浓度。应用多元回归分析建立MPA 0~12 h浓度曲线下面积(AUC_(0-12 h))的估算模型。选择相关系数高、临床应用方便的模型应用Bootstrap法及Bland-Altman法对其准确性进行验证。结果:3种免疫抑制方案MPA的AUC_(0-12)存在差异。应用Cs A+EC-MPS的患者MPA AUC_(0-12)为(54.66±26.86)ng·ml^(-1)·h,显著低于TAC+EC-MPS及TAC+MMF组(P<0.01)。经验证,Cs A+EC-MPS组较为理想的回归模型为1.32×C_1+0.54×C_(1.5)+1.25×C_2+3.21×C_4+12.53,r^2=0.75;TAC+MMF组为1.54×C_(0.5)+2.26×C_2+6.60×C_4-2.57,r^2=0.96;TAC+EC-MPS组为1.21×C_1+0.43×C_(1.5)+1.16×C_2+4.8×C_4+19.32,r^2=0.89。结论:MMF或EC-MPS在与Cs A或TAC联用会存在不同的药动学特征,应当应用不同的有限采样法MPA AUC_(0-12)估算公式,更为合理的评估MPA药物暴露。

Objective： To predict mycophenolic acid （MPA） exposure in renal transplant recipients treated with different immuno- suppressant regimens by establishing a limited sampling model. Methods： One hundred and eight patients were enrolled in the study. According to the immunosuppressant regimen, the patients were divided into cyclosporine A （ CsA ） ＋ enteric-coated myeophenolate sodium （EC-MPS） group （ n = 49）, taerolimus （ TAC ） ＋ mycophenolate mofetil （MMF） group （ n = 32） and TAC ＋ EC-MPS group （n = 27 ）. On the 14th day after the renal transplant operation, blood samples were collected before the treatment （0 h） and 0.5 h, 1 h, 1.5 h, 2 h, 4 h, 6 h, 8 h, 10 b and 12 h after MPA drug administration. LC-MS/MS was used to determine the MPA plasma con- centration. Multivariate regression analysis was used to establish models for the estimation of area under the MPA 0-12-hour concentra- tion curve （AUC0-12h ）. The models with high correlation coefficient and convenient clinical application were selected to be verified by Bootstrap method and Bland-Altman method. Results： The AUC0-12 of MPA after various immunosuppressive regimens was significantly different, and that was 54.66 ± 26.86 ng · ml - 1 · h in CsA ＋ EC-MPS group, which was significantly lower than that in TAC ＋ EC- MPS group and TAC ＋ MMF group （ P 〈 0.01 ）. The best regression model verified by Bootstrap method and Bland-Ahman method in CsA ＋ EC-MPS group was 1.32 ×C1 ＋0.54×C1.5 ＋ 1.25 × C2 ＋3.21 ×C2 ＋ 12.53, r2 =0.75; that in TAC ＋ MMF group was 1.54× C0.5 ＋2.26× C2＋6.60×C42.57, r2=0.96; that inTAC ＋ EC-MPSgroupwas1.21×C1 ＋0.43×C1.5＋1.16×C2＋4.8 × C4 ＋ 19.32, r2 = 0.89. Conclusion： Different pharmacokinetic characteristics are shown for MPA drugs MMF or EC-MPS in the combination with CsA or TAC. Different limited sampling strategy should be used to estimate AUC0-12 of MPA in order to evaluate MPA drug exposure more reasonably.