Le Louedec Félicien, Gallais Fanny, Thomas Fabienne, White-Koning Mélanie, Allal Ben, Protin Caroline, Ysebaert Loïc, Chatelut Étienne, Puisset Florent
Department of Pharmacology, Institut Claudius Régaud, Institut Universitaire du Cancer de Toulouse-Oncopole, 31059 Toulouse, France.
Cancer Research Center of Toulouse, Inserm UMR1037, 31037 Toulouse, France.
Pharmaceuticals (Basel). 2021 Feb 18;14(2):162. doi: 10.3390/ph14020162.
Therapeutic drug monitoring of ibrutinib is based on the area under the curve of concentration vs. time (AUC) instead of trough concentration (C) because of a limited accumulation in plasma. Our objective was to identify a limited sampling strategy (LSS) to estimate AUC associated with Bayesian estimation. The actual AUC of 85 patients was determined by the Bayesian analysis of the full pharmacokinetic profile of ibrutinib concentrations (pre-dose T0 and 0.5, 1, 2, 4 and 6 h post-dose) and experimental AUC were derived considering combinations of one to four sampling times. The T0-1-2-4 design was the most accurate LSS (root-mean-square error RMSE = 11.0%), and three-point strategies removing the 1 h or 2 h points (RMSE = 22.7% and 14.5%, respectively) also showed good accuracy. The correlation between the actual AUC and C was poor ( = 0.25). The joint analysis of dihydrodiol-ibrutinib metabolite concentrations did not improve the predictive performance of AUC. These results were confirmed in a prospective validation cohort ( = 27 patients). At least three samples, within the pre-dose and 4 h post-dose period, are necessary to estimate ibrutinib exposure accurately.
由于依鲁替尼在血浆中的蓄积有限，其治疗药物监测基于浓度-时间曲线下面积（AUC）而非谷浓度（C）。我们的目标是确定一种有限采样策略（LSS），以估计与贝叶斯估计相关的AUC。通过对依鲁替尼浓度的完整药代动力学曲线（给药前T0以及给药后0.5、1、2、4和6小时）进行贝叶斯分析，确定了85例患者的实际AUC，并考虑一至四个采样时间的组合得出实验性AUC。T0-1-2-4设计是最准确的LSS（均方根误差RMSE = 11.0%），去除1小时或2小时时间点的三点策略（RMSE分别为22.7%和14.5%）也显示出良好的准确性。实际AUC与C之间的相关性较差（= 0.25）。二氢二醇-依鲁替尼代谢物浓度的联合分析并未改善AUC的预测性能。这些结果在前瞻性验证队列（= 27例患者）中得到了证实。为了准确估计依鲁替尼的暴露量，在给药前和给药后4小时内至少需要三个样本。
