INSERM U850, University of Limoges, Limoges, France.
Clin Pharmacokinet. 2009;48(12):805-16. doi: 10.2165/11318080-000000000-00000.
The aims of this study were (i) to investigate the population pharmacokinetics of tacrolimus in renal transplant recipients, including the influence of biological and pharmacogenetic covariates; and (ii) to develop a Bayesian estimator able to reliably estimate the individual pharmacokinetic parameters and inter-dose area under the blood concentration-time curve (AUC) from 0 to 12 hours (AUC(12)) in renal transplant patients.
Full pharmacokinetic profiles were obtained from 32 renal transplant patients at weeks 1 and 2, and at months 1, 3 and 6 post-transplantation. The population pharmacokinetic analysis was performed using the nonlinear mixed-effect modelling software NONMEM version VI. Patients' genotypes were characterized by allelic discrimination for PXR -25385C>T genes.
Tacrolimus pharmacokinetics were well described by a two-compartment model combined with an Erlang distribution to describe the absorption phase, with low additive and proportional residual errors of 1.6 ng/mL and 9%, respectively. Both the haematocrit and PXR -25385C>T single nucleotide polymorphism (SNP) were identified as significant covariates for apparent oral clearance (CL/F) of tacrolimus, which allowed improvement of prediction accuracy. Specifically, CL/F decreased gradually with the number of mutated alleles for the PXR -25385C>T SNP and was inversely proportional to the haematocrit value. However, clinical criteria of relevance, mainly the decrease in interindividual variability and residual error, led us to retain only the haematocrit in the final model. Maximum a posteriori Bayesian forecasting allowed accurate prediction of the tacrolimus AUC(12) using only three sampling times (at 0 hour [predose] and at 1 and 3 hours postdose) in addition to the haematocrit value, with a nonsignificant mean AUC bias of 2% and good precision (relative mean square error = 11%).
Population pharmacokinetic analysis of tacrolimus in renal transplant recipients showed a significant influence of the haematocrit on its CL/F and led to the development of a Bayesian estimator compatible with clinical practice and able to accurately predict tacrolimus individual pharmacokinetic parameters and the AUC(12).
本研究的目的是（i）研究肾移植受者中环孢素的群体药代动力学，包括生物和遗传药理学因素的影响；（ii）开发一种贝叶斯估计器，能够可靠地估计肾移植患者的个体药代动力学参数和血药浓度-时间曲线下 0 至 12 小时（AUC（12））的剂量间面积。
在移植后第 1、2 周和第 1、3、6 个月时，从 32 名肾移植患者中获得全药代动力学曲线。使用 NONMEM 版本 VI 非线性混合效应建模软件进行群体药代动力学分析。通过等位基因鉴别法对 PXR-25385C>T 基因进行患者基因型特征分析。
环孢素药代动力学采用两室模型结合 Erlang 分布进行描述，吸收相的低加性和比例残留误差分别为 1.6ng/mL 和 9%。红细胞比容和 PXR-25385C>T 单核苷酸多态性（SNP）均被确定为环孢素表观口服清除率（CL/F）的显著协变量，这可以提高预测准确性。具体来说，随着 PXR-25385C>T SNP 突变等位基因数量的增加，CL/F 逐渐降低，与红细胞比容值呈反比。然而，临床相关标准，主要是个体间变异性和残留误差的降低，导致我们在最终模型中仅保留红细胞比容。最大后验贝叶斯预测仅使用三个采样时间（零时[预剂量]和给药后 1 小时和 3 小时）以及红细胞比容值，就可以准确预测环孢素 AUC（12），平均 AUC 偏差无统计学意义（2%），精度良好（相对均方误差=11%）。
肾移植受者中环孢素的群体药代动力学分析显示红细胞比容对其 CL/F 有显著影响，并开发了一种与临床实践兼容的贝叶斯估计器，能够准确预测环孢素的个体药代动力学参数和 AUC（12）。
