CHU Limoges, Universit de Limoges, Limoges, France.
Clin Pharmacokinet. 2012 Mar 1;51(3):175-86. doi: 10.2165/11594760-000000000-00000.
Therapeutic drug monitoring of tacrolimus is a major support to patient management and could help improve the outcome of lung transplant recipients, by minimizing the risk of rejections and infections. However, despite the wide use of tacrolimus as part of maintenance immunosuppressive regimens after lung transplantation, little is known about its pharmacokinetics in this population. Better knowledge of the pharmacokinetics of tacrolimus in lung transplant recipients, and the development of tools dedicated to its therapeutic drug monitoring, could thus help improve their outcome.
The aims of this study were (i) to characterize the population pharmacokinetics of tacrolimus in lung transplant recipients, including the influence of biological and pharmacogenetic covariates; and (ii) to develop a Bayesian estimator of the tacrolimus area under the blood concentration-time curve from time zero to 12 hours (AUC(12)) for its therapeutic drug monitoring in lung transplant recipients.
A population pharmacokinetic model was developed by nonlinear mixed-effects modelling using NONMEM® version VI, from 182 tacrolimus full concentration-time profiles collected in 78 lung transplant recipients within the first year post-transplantation. Patient genotypes for the cytochrome P450 3A5 (CYP3A5) A6986G single nucleotide polymorphism (SNP) were characterized by TaqMan allelic discrimination. Patients were divided into an index dataset (n = 125 profiles) and a validation dataset (n = 57 profiles). A Bayesian estimator was derived from the final model using the index dataset, in order to determine the tacrolimus AUC(12) on the basis of a limited number of samples. The predictive performance of the Bayesian estimator was evaluated in the validation dataset by comparing the estimated AUC(12) with the trapezoidal AUC(12).
Tacrolimus pharmacokinetics were described using a two-compartment model with Erlang absorption and first-order elimination. The model included cystic fibrosis (CF) and CYP3A5 polymorphism as covariates. The relative bioavailability in patients with CF was approximately 60% of the relative bioavailability observed in patients without CF, and the transfer rate constant between the transit compartments was 2-fold smaller in patients with CF than in those without CF (3.32 vs 7.06 h-1). The apparent clearance was 40% faster in CYP3A5 expressers than in non-expressers (24.5 vs 17.5 L/h). Good predictive performance was obtained with the Bayesian estimator developed using the final model and concentrations measured at 40 minutes and at 2 and 4 hours post-dose, as shown by the mean bias (1.1%, 95% CI -1.4, 3.7) and imprecision (9.8%) between the estimated and the trapezoidal AUC(12). The bias was >20% in 1.8% of patients.
Population pharmacokinetic analysis showed that lung transplant patients with CF displayed lower bioavailability and a smaller transfer rate constant between transit compartments than those without CF, while the apparent clearance was faster in CYP3A5 expressers than in non-expressers. The Bayesian estimator developed in this study provides an accurate prediction of tacrolimus exposure in lung transplant patients, with and without CF, throughout the first year post-transplantation. This tool may allow routine tacrolimus dose individualization and may be used to conduct clinical trials on therapeutic drug monitoring of tacrolimus after lung transplantation.
他克莫司的治疗药物监测是患者管理的主要支持手段，可以帮助减少肺移植受者的排斥反应和感染风险，从而改善其预后。然而，尽管他克莫司在肺移植后作为维持免疫抑制方案的一部分被广泛使用，但对于该人群的药代动力学却知之甚少。更好地了解肺移植受者中他克莫司的药代动力学，并开发专门用于其治疗药物监测的工具，可能有助于改善他们的预后。
本研究的目的是：(i)描述肺移植受者中他克莫司的群体药代动力学特征，包括生物和药代遗传学因素的影响；(ii)为其治疗药物监测开发一种从时间零到 12 小时的他克莫司血药浓度-时间曲线下面积（AUC(12)）的贝叶斯估算器。
采用 NONMEM® 版本 VI 进行非线性混合效应建模，对 78 例肺移植受者移植后 1 年内采集的 182 份全浓度-时间曲线进行了群体药代动力学模型的建立。通过 TaqMan 等位基因鉴别法对细胞色素 P450 3A5（CYP3A5）A6986G 单核苷酸多态性（SNP）的患者基因型进行了描述。患者分为指数数据集（n=125 个曲线）和验证数据集（n=57 个曲线）。利用指数数据集，从最终模型中推导出贝叶斯估算器，以根据有限的样本量确定他克莫司的 AUC(12)。通过比较贝叶斯估算器与梯形 AUC(12)，在验证数据集中评估了贝叶斯估算器的预测性能。
采用两室模型加 Erlang 吸收和一级消除描述他克莫司的药代动力学。模型包括囊性纤维化（CF）和 CYP3A5 多态性作为协变量。CF 患者的相对生物利用度约为无 CF 患者的 60%，CF 患者的转运室之间的转移速率常数是无 CF 患者的两倍（3.32 比 7.06/h）。CYP3A5 表达者的表观清除率比非表达者快 40%（24.5 比 17.5/L/h）。使用最终模型和在给药后 40 分钟以及 2 小时和 4 小时测量的浓度开发的贝叶斯估算器具有良好的预测性能，表现为估计和梯形 AUC(12)之间的平均偏差（1.1%，95%CI -1.4，3.7）和不精密度（9.8%）。在 1.8%的患者中，偏差>20%。
群体药代动力学分析表明，与无 CF 的患者相比，CF 肺移植患者的生物利用度较低，转运室之间的转移速率常数较小，而 CYP3A5 表达者的表观清除率较快。本研究中开发的贝叶斯估算器可准确预测肺移植患者，包括 CF 患者和非 CF 患者，在移植后 1 年内的他克莫司暴露情况。该工具可用于肺移植后他克莫司治疗药物监测的个体化剂量调整，并可用于临床试验。
