Monchaud C, Rousseau A, Leger F, David O J, Debord J, Dantoine T, Marquet P
Department of Pharmacology and Toxicology, University Hospital, 2 Avenue Martin Luther King, 87042, Limoges, France.
Eur J Clin Pharmacol. 2003 Apr;58(12):813-20. doi: 10.1007/s00228-003-0559-5. Epub 2003 Mar 6.
The aim of this study was to develop routinely applicable limited sampling strategies for assessing cyclosporin (CsA) AUC(0-12 h), and possibly other exposure indices such as AUC(0-4 h) and C(max), in heart transplant patients over the first year post-transplantation.
First, the individual pharmacokinetics (PKs) of 14 adult heart-transplant patients receiving Neoral were assessed at three post-transplantation periods, at the end of the first week (W1), the third month (M3) and the first year (Y1). To fit blood concentrations, a PK model specially developed for oral CsA was applied. Second, two statistical methods were compared for AUC(0-12 h) estimation using a limited sampling strategy (maximum of three blood samples): multiple regression analysis (MR) and Bayesian estimation (BE).
No significant difference was observed between the individual PK parameters at M3 and Y1, so population modelling was performed taking as a whole the concentration data collected at M3 and Y1. On the contrary, a significant difference ( P<0.05) was found for the C2/dose ratio between W1 and M3 and between W1 and Y1 (mean+/-SD =5.47+/-2.33; 7.78+/-1.05; 6.98+/-2.17 ml(-1 )for W1, M3 and Y1, respectively). Also, C(max)/dose and A were found significantly lower at W1 than at M3 ( P<0.01 and P<0.005, respectively), while lambda(1) was significantly higher at W1 than at both M3 and Y1 ( P<0.01). Using three sampling times (t0 h, t1 h and t3 h), BE allowed an accurate prediction of AUC(0-12 h) (mean bias =3.06+/-12.16%; +1.50+/-1.61%; and -0.20+/-11.42% at W1, M3 and Y1, respectively), AUC(0-4 h )and C(max). MR led to satisfactory estimation of AUC(0-12 h) using only two blood samples collected 2 h and 6 h post-dose (R=0.956-0.993; bias =-5.22 to +4.41; precision =6.38 to 9.90%), but this method is unable to estimate any other exposure index and requires strict respect of sampling times, contrary to BE.
Neoral monitoring based on full or abbreviated AUC is possible using BE or MR in heart transplant patients over the first year post-transplantation. BE provides a good description of the individual PK profiles and thus might be useful not only in case of potential discrepancies between C2 and clinical findings, but also for clinical trials aimed at finding optimum PK monitoring in heart recipients.
本研究旨在制定常规适用的有限采样策略，用于评估心脏移植患者移植后第一年的环孢素（CsA）药时曲线下面积（AUC(0 - 12 h)），以及可能的其他暴露指数，如AUC(0 - 4 h)和血药浓度峰值（C(max)）。
首先，在移植后三个时期，即第一周（W1）末、第三个月（M3）和第一年（Y1），评估14例接受新山地明（Neoral）的成年心脏移植患者的个体药代动力学（PK）。为拟合血药浓度，应用了专门为口服CsA开发的PK模型。其次，比较了两种统计方法在使用有限采样策略（最多三个血样）估算AUC(0 - 12 h)时的效果：多元回归分析（MR）和贝叶斯估计（BE）。
M3和Y1时的个体PK参数之间未观察到显著差异，因此将M3和Y1收集的浓度数据作为一个整体进行群体建模。相反，W1与M3之间以及W1与Y1之间的C2/剂量比值存在显著差异（P<0.05）（W1、M3和Y1时的均值±标准差分别为5.47±2.33；7.78±1.05；6.98±2.17 ml⁻¹）。此外，发现W1时的C(max)/剂量和A显著低于M3时（分别为P<0.01和P<0.005），而W1时的λ₁显著高于M3和Y1时（P<0.01）。使用三个采样时间点（t0 h、t1 h和t3 h），BE能够准确预测AUC(0 - 12 h)（W1、M3和Y1时的平均偏差分别为3.06±12.16%； +1.50±1.61%；和 -0.20±11.42%）、AUC(0 - 4 h)和C(max)。MR仅使用给药后2 h和6 h采集的两个血样就能对AUC(0 - 12 h)进行令人满意的估算（R = 0.956 - 0.993；偏差 = -5.22至 +4.41；精密度 = 6.38至9.90%），但与BE不同，该方法无法估算任何其他暴露指数，且需要严格遵守采样时间。
在心脏移植患者移植后的第一年，使用BE或MR基于完整或简化的AUC进行新山地明监测是可行的。BE能很好地描述个体PK特征，因此不仅在C2与临床结果可能存在差异的情况下有用，而且对于旨在寻找心脏受体最佳PK监测的临床试验也可能有用。
