阿达替尼是一种二代BCR-ABL1酪氨酸激酶抑制剂，用于一线治疗载有费城染色体阳性的慢性髓细胞性白血病(CML)，其药代动力学（PK）变异性较高。然而，迄今为止，中国CML患者的阿达替尼PK数据鲜有报道。因此，我们在中国CML患者中开发了一种阿达替尼的群体药代动力学（PPK）模型，并确定了能够解释PK个体变异的相关变量，以实现最佳的个体给药策略。阿达替尼的PPK模型基于140例CML患者的754个血浆浓度进行，分析了各种遗传和物化参数。我们使用Phoenix NLME的非线性混合效应（NLME）进行了建模。最终开发的模型经过了内部和外部验证。蒙特卡罗模拟用于预测不同剂量情况下达到稳态的药物暴露。阿达替尼的PK采用两室及对数加法残差误差模型进行了很好的描述。本研究中的患者的CL/F估计相对较低（126 L/h）。发现了年龄与阿达替尼的CL/F之间的显著关联，并将其纳入了最终模型。没有证实任何的遗传因素是阿达替尼的显著相关变量。与36名患者共140个样本进行的外部验证结果是可接受的。模拟结果显示，老年患者的暴露程度显著增加。本研究的结果表明，对于中国患者，较低剂量的阿达替尼更适合，并且随着年龄的增加，尤其是对于老年患者，剂量可以适当减少。© 2023. 作者（们）在Springer Science+Business Media, LLC, part of Springer Nature下独家许可。

Dasatinib, a second-generation tyrosine kinase inhibitor of BCR-ABL 1, used for first-line treatment of Philadelphia chromosome-positive chronic myeloid leukemia (CML), exhibits high pharmacokinetic (PK) variability. However, its PK data in Chinese patients with CML remains rarely reported to date. Thus, we developed a population pharmacokinetic (PPK) model of dasatinib in Chinese patients and identified the covariate that could explain the individual variability of PK for optimal individual administration.PPK modeling for dasatinib was performed based on 754 plasma concentrations obtained from 140 CML patients and analysis of various genetic and physicochemical parameters. Modeling was performed with nonlinear mixed-effects (NLME) using Phoenix NLME. The finally developed model was evaluated using internal and external validation. Monte Carlo simulations were used to predict drug exposures at a steady state for various dosages.The PK of dasatinib were well described by a two-compartment with a log-additive residual error model. Patients in the current study had a relatively low estimate of CL/F (126 L/h). A significant association was found between the covariate of age and CL/F of dasatinib, which was incorporated into the final model. None of the genetic factors was confirmed as a significant covariate for dasatinib. The results of external validation with 140 samples from 36 patients were acceptable. Simulation results showed significantly higher exposures in elderly patients.This study's findings suggested that low-dose dasatinib would be better suited for Chinese patients, and the dosage can be appropriately reduced according to the increase of age, especially for the elderly.© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.