Li Xiaoqing, Bo Yunhai, Yin Han, Liu Xiaohong, Li Xu, Yang Fen
Key laboratory of Carcinogenesis and Translational Research (Ministry of Education), National drug clinical trial center, Peking University Cancer Hospital & Institute, Beijing, China.
Chia Tai Tianqing Pharmaceutical Group Co Ltd, Nanjing, Jiangsu, China.
Front Pharmacol. 2023 Jan 16;14:1102244. doi: 10.3389/fphar.2023.1102244. eCollection 2023.
TQ-B3203 is a novel topoisomerase I inhibitor currently in development for the treatment of advanced solid tumors. Great differences in pharmacokinetic characteristics were found among individuals according to the phase I clinical trial following intravenous administration of TQ-B3203 liposome injection (TLI) in Chinese patients with advanced solid tumors. Thus, it is significant to establish a population pharmacokinetic model to find the key factors and recognize their effect on pharmacokinetic parameters in order to guide individualized administration. Non-linear mixed effect models were developed using the plasma concentrations obtained from the phase I clinical trial by implementing the Phoenix NLME program. Covariates that may be related to pharmacokinetics were screened using stepwise methods. The final model was validated by goodness-of-fit plots, visual predictive check, non-parametric bootstrap and a test of normalized prediction distribution errors. A three-compartment model with first-order elimination was selected as the best structural model to describe TQ-B3203 disposition adequately. Direct bilirubin (DBIL) and body mass index (BMI) were the two most influential factors on clearance, while lean body weight (LBW) was considered to affect the apparent distribution volume of the central compartment. The population estimations of clearance and central volume were typical at 3.97 L/h and 4.81 L, respectively. Model-based simulations indicated that LBW had a great impact on C, BMI exerted a considerable influence on AUC, and the significance of DBIL on both AUC and C was similarly excellent. The first robust population pharmacokinetic model of TQ-B3203 was successfully generated following intravenous administration of TLI in Chinese patients with advanced solid tumors. BMI, LBW and DBIL were significant covariates that affected the pharmacokinetics of TQ-B3203. This model could provide references for the dose regimen in the future study of TLI.
TQ-B3203是一种新型拓扑异构酶I抑制剂，目前正处于研发阶段，用于治疗晚期实体瘤。在中国晚期实体瘤患者中静脉注射TQ-B3203脂质体注射液（TLI）后的I期临床试验表明，个体间的药代动力学特征存在很大差异。因此，建立群体药代动力学模型以找出关键因素并认识其对药代动力学参数的影响，从而指导个体化给药具有重要意义。通过实施Phoenix NLME程序，利用I期临床试验获得的血浆浓度建立了非线性混合效应模型。采用逐步法筛选可能与药代动力学相关的协变量。通过拟合优度图、可视化预测检查、非参数自抽样法和标准化预测分布误差检验对最终模型进行验证。选择具有一级消除的三室模型作为最佳结构模型，以充分描述TQ-B3203的处置过程。直接胆红素（DBIL）和体重指数（BMI）是对清除率影响最大的两个因素，而瘦体重（LBW）被认为会影响中央室的表观分布容积。清除率和中央室容积的群体估计值分别为3.97 L/h和4.81 L，较为典型。基于模型的模拟表明，LBW对C有很大影响，BMI对AUC有相当大的影响，DBIL对AUC和C的影响同样显著。在中国晚期实体瘤患者静脉注射TLI后，成功建立了首个稳健的TQ-B3203群体药代动力学模型。BMI、LBW和DBIL是影响TQ-B3203药代动力学的重要协变量。该模型可为TLI未来研究中的给药方案提供参考。
