Department of Pharmacy, Peking University People's Hospital, No. 11 Xizhimen South StreetXicheng District, Beijing, 100044, China.
Department of Pharmacy Administration and Clinical Pharmacy, School of Pharmaceutical Sciences, Peking University, Beijing, China.
Pharm Res. 2023 Oct;40(10):2413-2422. doi: 10.1007/s11095-023-03603-z. Epub 2023 Sep 19.
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.
达沙替尼是一种第二代 BCR-ABL1 酪氨酸激酶抑制剂，用于治疗费城染色体阳性慢性髓性白血病（CML）的一线治疗，表现出高度的药代动力学（PK）变异性。然而，迄今为止，在中国 CML 患者中，其 PK 数据报道甚少。因此，我们开发了达沙替尼在中国患者中的群体药代动力学（PPK）模型，并确定了能够解释 PK 个体差异的协变量，以实现最佳个体给药。
对 140 例 CML 患者的 754 个血浆浓度进行达沙替尼的 PPK 建模，并分析了各种遗传和物理化学参数。使用 Phoenix NLME 进行非线性混合效应（NLME）建模。使用内部和外部验证评估最终开发的模型。使用蒙特卡罗模拟预测各种剂量下稳态的药物暴露量。
达沙替尼的 PK 采用两室模型和对数相加残差模型得到了很好的描述。本研究中的患者 CL/F（126 L/h）估计值相对较低。达沙替尼 CL/F 的协变量与年龄之间存在显著相关性，该协变量被纳入最终模型。没有发现遗传因素是达沙替尼的显著协变量。用 36 例患者的 140 个样本进行的外部验证结果是可以接受的。模拟结果表明，老年患者的暴露量明显更高。
本研究结果表明，低剂量达沙替尼更适合中国患者，并且可以根据年龄的增加适当减少剂量，特别是对于老年人。
