BACKGROUND AND OBJECTIVE Ibrutinib is used for the treatment of chronic lymphocytic leukemia and other lymphoid malignancies. The aim of this work is to develop a population pharmacokinetic model for ibrutinib and its dihydrodiol metabolite to quantify pharmacokinetic inter- and intra-individual variability, to evaluate the impact of several covariates on ibrutinib pharmacokinetic parameters, and to examine the relationship between exposure and clinical outcome. METHODS Patients treated with ibrutinib were included in the study and followed up for 2 years. Pharmacokinetic blood samples were taken from months 1 to 12 after inclusion. Ibrutinib and dihydrodiol-ibrutinib concentrations were assessed using ultra-performance liquid chromatography tandem mass spectrometry. A population pharmacokinetic model was developed using NONMEM version 7.4. RESULTS A total of 89 patients and 1501 plasma concentrations were included in the pharmacokinetic analysis. The best model consisted in two compartments for each molecule. Absorption was described by a sequential zero first-order process and a lag time. Ibrutinib was either metabolised into dihydrodiol-ibrutinib or excreted through other elimination routes. A link between the dosing compartment and the dihydrodiol-ibrutinib central compartment was added to assess for high first-pass hepatic metabolism. Ibrutinib clearance had 67% and 47% inter- and intra-individual variability, respectively, while dihydrodiol-ibrutinib clearance had 51% and 26% inter- and intra-individual variability, respectively. Observed ibrutinib exposure is significantly higher in patients carrying one copy of the cytochrome P450 3A4*22 variant (1167 ng.h/mL vs 743 ng.h/mL, respectively, p = 0.024). However, no covariates with a clinically relevant effect on ibrutinib or dihydrodiol-ibrutinib exposure were identified in the PK model. An external evaluation of the model was performed. Clinical outcome was expressed as the continuation or discontinuation of ibrutinib therapy 1 year after treatment initiation. Patients who had treatment discontinuation because of toxicity had significantly higher ibrutinib area under the curve (p = 0.047). No association was found between cessation of therapy due to disease progression and ibrutinib area under the curve in patients with chronic lymphocytic leukemia. For the seven patients with mantle cell lymphoma studied, an association trend was observed between disease progression and low exposure to ibrutinib. CONCLUSIONS We present the first population pharmacokinetic model describing ibrutinib and dihydrodiol-ibrutinib concentrations simultaneously. Large inter-individual variability and substantial intra-individual variability were estimated and could not be explained by any covariate. Higher plasma exposure to ibrutinib is associated with cessation of therapy due to the occurrence of adverse events within the first year of treatment. The association between disease progression and ibrutinib exposure in patients with mantle cell lymphoma should be further investigated. TRIAL REGISTRATION ClinicalTrials.gov no. NCT02824159.

中文翻译：

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依鲁替尼及其二氢二醇代谢物在淋巴恶性肿瘤患者中的群体药代动力学。

背景和目的 依鲁替尼用于治疗慢性淋巴细胞白血病和其他淋巴系统恶性肿瘤。这项工作的目的是开发依鲁替尼及其二氢二醇代谢物的群体药代动力学模型，以量化个体间和个体内的药代动力学变异性，评估几个协变量对依鲁替尼药代动力学参数的影响，并检查暴露与临床之间的关系。结果。方法 接受依鲁替尼治疗的患者被纳入研究并随访 2 年。在纳入后第 1 至 12 个月采集药代动力学血样。使用超高效液相色谱串联质谱法评估依鲁替尼和二氢二醇-依鲁替尼浓度。使用 NONMEM 7.4 版开发了群体药代动力学模型。结果 总共 89 名患者和 1501 个血浆浓度被纳入药代动力学分析。最好的模型由每个分子的两个隔室组成。吸收由连续零一阶过程和滞后时间描述。依鲁替尼被代谢成二氢二醇-依鲁替尼或通过其他消除途径排出体外。添加了给药隔室和二氢二醇-依鲁替尼中央隔室之间的链接以评估高首过肝脏代谢。依鲁替尼的清除率分别具有 67% 和 47% 的个体间和个体内变异性，而二氢二醇-依鲁替尼的清除率分别具有 51% 和 26% 的个体间和个体内变异性。在携带一份细胞色素 P450 3A4*22 变异体的患者中观察到的依鲁替尼暴露量显着更高（1167 ng.h/mL vs 743 ng.h/mL，分别为 p = 0.024）。然而，在 PK 模型中没有发现对依鲁替尼或二氢二醇-依鲁替尼暴露具有临床相关影响的协变量。对该模型进行了外部评估。临床结果表示为治疗开始后 1 年继续或停止依鲁替尼治疗。由于毒性而停止治疗的患者的依鲁替尼曲线下面积显着更高（p = 0.047）。在慢性淋巴细胞白血病患者中，未发现因疾病进展而停止治疗与依鲁替尼曲线下面积之间存在关联。对于所研究的 7 名套细胞淋巴瘤患者，观察到疾病进展与依鲁替尼低暴露之间存在关联趋势。结论 我们提出了第一个同时描述依鲁替尼和二氢二醇-依鲁替尼浓度的群体药代动力学模型。估计了较大的个体间变异性和显着的个体内部变异性，并且无法用任何协变量来解释。由于在治疗的第一年内发生不良事件，较高的依鲁替尼血浆暴露与停止治疗有关。应进一步研究套细胞淋巴瘤患者疾病进展与依鲁替尼暴露之间的关联。试验注册 ClinicalTrials.gov 编号。NCT02824159。由于在治疗的第一年内发生不良事件，较高的依鲁替尼血浆暴露与停止治疗有关。应进一步研究套细胞淋巴瘤患者疾病进展与依鲁替尼暴露之间的关联。试验注册 ClinicalTrials.gov 编号。NCT02824159。由于在治疗的第一年内发生不良事件，较高的依鲁替尼血浆暴露与停止治疗有关。应进一步研究套细胞淋巴瘤患者疾病进展与依鲁替尼暴露之间的关联。试验注册 ClinicalTrials.gov 编号。NCT02824159。