Gallais Fanny, Ysebaert Loïc, Despas Fabien, De Barros Sandra, Obéric Lucie, Allal Ben, Chatelut Etienne, White-Koning Mélanie
Cancer Research Center of Toulouse, INSERM UMR-1037, CNRS ERL5294, Paul Sabatier University, Toulouse, France.
Department of Hematology, Institut Universitaire du Cancer de Toulouse - Oncopole, Toulouse, France.
Clin Pharmacol Ther. 2021 Jul;110(1):220-228. doi: 10.1002/cpt.2189. Epub 2021 Mar 3.
Ibrutinib is indicated for the treatment of chronic lymphocytic leukemia (CLL). Absolute lymphocyte count (ALC) is a clinical criterion used for the monitoring of CLL. Ibrutinib has several effects on lymphocytes, and has highly variable pharmacokinetics (PK). The objective of this work was to build a PK-pharmacodynamic (PD) model describing ALC dynamics under ibrutinib treatment in patients with CLL. ALC observations before and after ibrutinib treatment initiation in patients with CLL were included in the analysis. A population PK-PD model was developed based on physio-pharmacological knowledge. Individual PK concentrations at each hospital visit were included in the model. The association between PD parameters and lymphocytosis, and between PD parameters and response to treatment were assessed. A total of 94 patients, 658 ALC and 1,501 PK observations were included in model development. The final PK-PD model accurately described ALC dynamics for different patient profiles. It consisted in two compartments (tissues and blood circulation) with ibrutinib plasmatic concentration inducing two drug effects: stimulation of lymphocyte redistribution and death. Patients with hyperlymphocytosis had significantly higher tissues to circulation baseline lymphocyte count ratio, and lower death effect. Patients who progressed under ibrutinib had significantly lower baseline lymphocyte counts in tissues (2-fold lower) and blood (3-fold lower). The first PK-PD model for ALC in patients with CLL under ibrutinib treatment was developed. This model suggests that estimated lymphocyte counts in tissues and blood could be used as an early predictor of response in patients with CLL.
伊布替尼适用于治疗慢性淋巴细胞白血病（CLL）。绝对淋巴细胞计数（ALC）是用于监测CLL的一项临床标准。伊布替尼对淋巴细胞有多种作用，并且具有高度可变的药代动力学（PK）。这项工作的目的是建立一个PK-药效学（PD）模型，描述CLL患者在伊布替尼治疗下的ALC动态变化。分析纳入了CLL患者在开始伊布替尼治疗前后的ALC观察数据。基于生理药理学知识建立了群体PK-PD模型。每次医院就诊时的个体PK浓度都纳入了模型。评估了PD参数与淋巴细胞增多之间的关联，以及PD参数与治疗反应之间的关联。模型开发共纳入了94例患者、658次ALC观察数据和1501次PK观察数据。最终的PK-PD模型准确地描述了不同患者特征下的ALC动态变化。它由两个隔室（组织和血液循环）组成，伊布替尼血浆浓度产生两种药物效应：刺激淋巴细胞重新分布和死亡。淋巴细胞增多症患者的组织与循环基线淋巴细胞计数比值显著更高，而死亡效应更低。在伊布替尼治疗下病情进展的患者，其组织中的基线淋巴细胞计数显著更低（低2倍），血液中的基线淋巴细胞计数也显著更低（低3倍）。建立了首个用于描述伊布替尼治疗下CLL患者ALC的PK-PD模型。该模型表明，组织和血液中估计的淋巴细胞计数可作为CLL患者治疗反应的早期预测指标。
