Department of Pharmacology, Toxicology and Pharmacovigilance, CHU Limoges, University Hospital of Limoges, CBRS, Limoges, France.
IPPRITT, Université de Limoges, INSERM, Limoges, France.
Clin Pharmacokinet. 2021 May;60(5):611-622. doi: 10.1007/s40262-020-00959-y. Epub 2020 Nov 24.
Tacrolimus has a narrow therapeutic range and requires dose adjustment, usually based on the trough blood concentration but preferably on the area under the concentration-time curve over 12 h post-dose (AUC). The single-arm, multicentre, clinical study IMPAKT aimed: (i) to develop, in de novo kidney transplant recipients, pharmacokinetic models and maximum a-posteriori Bayesian estimators for a generic, immediate-release, oral formulation of tacrolimus to estimate tacrolimus AUC at different post-transplant periods using a limited sampling strategy, and considering the CYP3A5*3 polymorphism as a covariate and (ii) to compare the performance of these Bayesian estimators to those previously developed for the original formulation.
Thirty patients were enrolled and 29 provided nine blood samples over 9 h at day 7 and months 1 and 3 post-transplant. Tacrolimus blood profiles measured with liquid chromatography-tandem mass spectrometry were modelled using one-compartment, double gamma absorption, linear elimination models developed in-house. Different limited sampling strategies of three time-points within 4 h post-dose were tested for the maximum a-posteriori Bayesian estimator of tacrolimus AUC. The models and estimators were validated internally and their performance compared to that of models previously developed for the original formulation.
The concentration-time curves, AUC/dose and trough blood concentration/dose exhibited wide inter-individual variability. The covariate-free pharmacokinetic models developed for the three post-transplant periods closely fitted the individual profiles. Maximum a-posteriori Bayesian estimators based on three different limited sampling strategies and no covariate yielded accurate AUC estimates, including for the five cytochrome P450 3A5 expressers and for the four patients without corticosteroids. The 0-1 h-3 h strategy finally chosen had very low bias (- 4.0 to - 2.5%) and imprecision (root mean square error 5.5-9.2%). The maximum a-posteriori Bayesian estimators previously developed for the reference product fitted the generic profiles with similar performance.
We developed original pharmacokinetic models and accurate maximum a-posteriori Bayesian estimators to estimate patient exposure and adjust the dose of generic tacrolimus, and confirmed that the robust tools previously developed for the original formulation can be applied to this generic.
他克莫司的治疗范围较窄，需要进行剂量调整，通常基于谷浓度，但最好是基于给药后 12 小时的浓度-时间曲线下面积（AUC）。这项单臂、多中心临床研究 IMPAKT 的目的是：（i）在新诊断的肾移植受者中，开发一种用于通用、速释、口服他克莫司的药代动力学模型和最大后验贝叶斯估计器，以使用有限采样策略在不同的移植后时期估计他克莫司 AUC，并考虑 CYP3A5*3 多态性作为协变量，（ii）比较这些贝叶斯估计器的性能与之前为原始配方开发的性能。
共纳入 30 例患者，其中 29 例在移植后第 7 天、第 1 个月和第 3 个月时提供了 9 次血样，共 9 小时。使用液相色谱-串联质谱法测量他克莫司血药浓度，使用内部开发的单室、双伽马吸收、线性消除模型进行建模。测试了 4 小时内 3 个时间点的不同有限采样策略，用于最大后验贝叶斯估计他克莫司 AUC。对三种移植后时期的无协变量药代动力学模型进行了内部验证，并与之前为原始配方开发的模型进行了比较。
浓度-时间曲线、AUC/剂量和谷浓度/剂量表现出广泛的个体间变异性。为三个移植后时期开发的无协变量药代动力学模型与个体曲线拟合良好。基于三种不同有限采样策略和无协变量的最大后验贝叶斯估计器得出了准确的 AUC 估计值，包括 5 例细胞色素 P450 3A5 表达者和 4 例无皮质激素患者。最终选择的 0-1 h-3 h 策略具有非常低的偏倚（-4.0 至-2.5%）和不精确性（均方根误差 5.5-9.2%）。之前为参比产品开发的最大后验贝叶斯估计器对通用产品的拟合性能相似。
我们开发了原始的药代动力学模型和准确的最大后验贝叶斯估计器，以估计患者的暴露量并调整通用他克莫司的剂量，并证实之前为原始配方开发的稳健工具可应用于该通用配方。
