Department of Laboratory Medicine, Semmelweis University, 4 Nagyvárad tér, 1089 Budapest, Hungary.
Department of Internal Medicine and Hematology, Semmelweis University, 46 Szentkirályi utca, 1088 Budapest, Hungary.
Molecules. 2022 Jul 25;27(15):4766. doi: 10.3390/molecules27154766.
Ibrutinib (IBR) is an oral anticancer medication that inhibits Bruton tyrosine kinase irreversibly. Due to the high risk of adverse effects and its pharmacokinetic variability, the safe and effective use of IBR is expected to be facilitated by precision dosing. Delivering suitable clinical laboratory information on IBR is a prerequisite of constructing fit-for-purpose population and individual pharmacokinetic models. The validation of a dedicated high-throughput method using liquid chromatography-mass spectrometry is presented for the simultaneous analysis of IBR and its pharmacologically active metabolite dihydrodiol ibrutinib (DIB) in human plasma. The 6 h benchtop stability of IBR, DIB, and the active moiety (IBR+DIB) was assessed in whole blood and in plasma to identify any risk of degradation before samples reach the laboratory. In addition, four regression algorithms were tested to determine the optimal assay error equations of IBR, DIB, and the active moiety, which are essential for the correct estimation of the error of their future nonparametric pharmacokinetic models. The noncompartmental pharmacokinetic properties of IBR and the active moiety were evaluated in three patients diagnosed with chronic lymphocytic leukemia to provide a proof of concept. The presented methodology allows clinical laboratories to efficiently support pharmacokinetics-based precision pharmacotherapy with IBR.
伊布替尼（IBR）是一种口服抗癌药物，可不可逆地抑制布鲁顿酪氨酸激酶。由于不良反应风险高且药代动力学变异性大，预计通过精准剂量来促进 IBR 的安全有效使用。提供关于 IBR 的合适临床实验室信息是构建适合目的人群和个体药代动力学模型的前提。本文提出了一种使用液相色谱-质谱联用的专用高通量方法，用于同时分析人血浆中的 IBR 及其具有药理活性的代谢物二氢二醇伊布替尼（DIB）。评估了 IBR、DIB 和活性部分（IBR+DIB）在全血和血浆中的 6 小时台式稳定性，以确定在样本到达实验室之前是否有任何降解风险。此外，还测试了四种回归算法，以确定 IBR、DIB 和活性部分的最佳测定误差方程，这对于正确估计其未来非参数药代动力学模型的误差至关重要。评估了三种诊断为慢性淋巴细胞白血病的患者的 IBR 和活性部分的非房室药代动力学特性，以提供概念验证。所提出的方法使临床实验室能够有效地支持基于药代动力学的 IBR 精准治疗。
