School of Pharmacy, Nanchang University, Nanchang, People's Republic of China.
Department of Pharmacy, The First Affiliated Hospital of Nanchang University, Nanchang, People's Republic of China.
Drug Des Devel Ther. 2023 Mar 14;17:809-820. doi: 10.2147/DDDT.S400986. eCollection 2023.
Imatinib is the first-line treatment for patients with gastrointestinal stromal tumors (GIST) after surgery. However, its pharmacokinetic profile varies remarkably between individuals and has not been well characterized in postoperative Chinese patients with GIST. Therefore, this study aimed to develop a population pharmacokinetic (PPK) model and recommend appropriate doses for different patients to achieve the target trough concentration in such a population.
A total of 110 surgically treated GIST patients were enrolled, of which 85 were applied to conduct a PPK analysis with a nonlinear mixed-effect model and 25 for external validation of the model. Demographic and biomedical covariates, as well as six single nucleotide polymorphisms were tested to explore the sources of variation in pharmacokinetic parameters of imatinib. Monte Carlo simulations were performed to establish the initial dosing regimens.
A one-compartment model was established in postoperative GIST patients. The red blood cell count (RBC) and rs2231142 were observed to have a significant effect on the clearance of imatinib. The typical values estimated by the final model were 9.72 L/h for clearance (CL/F) and 229 L for volume of distribution (V/F). Different from the fixed dose regimen of 400 mg each day, patients carrying rs2231142 heterozygous type and with a lower level of RBC (2.9 × 10/L), 300 mg imatinib daily is enough to achieve the target trough concentration. When RBC rises to 4.9 × 10/L, 500 mg daily is recommended. For patients with rs2231142 GG genotype, 500 mg a day is required at RBCs of 3.9 × 10/L and 4.9 × 10/L.
RBC and rs2231142 contribute to the pharmacokinetic variation of imatinib and personalized dose recommendations based on patient characteristics may be necessary.
伊马替尼是胃肠道间质瘤（GIST）患者手术后的一线治疗药物。然而，其药代动力学特征在个体之间差异显著，在中国 GIST 术后患者中尚未得到很好的描述。因此，本研究旨在建立一个群体药代动力学（PPK）模型，并为该人群中的不同患者推荐合适的剂量以达到目标谷浓度。
共纳入 110 例接受手术治疗的 GIST 患者，其中 85 例用于进行非线性混合效应模型的 PPK 分析，25 例用于模型的外部验证。检测了人口统计学和生物医学协变量以及 6 个单核苷酸多态性，以探讨伊马替尼药代动力学参数的变异来源。进行蒙特卡罗模拟以建立初始给药方案。
在 GIST 术后患者中建立了一个单室模型。红细胞计数（RBC）和 rs2231142 观察到对伊马替尼清除率有显著影响。最终模型估计的典型值分别为清除率（CL/F）的 9.72 L/h 和分布容积（V/F）的 229 L。与每天 400 mg 的固定剂量方案不同，携带 rs2231142 杂合子且 RBC 水平较低（2.9×10/L）的患者，每天 300 mg 伊马替尼即可达到目标谷浓度。当 RBC 上升到 4.9×10/L 时，推荐每天 500 mg。对于 rs2231142 GG 基因型的患者，在 RBC 为 3.9×10/L 和 4.9×10/L 时，每天需要 500 mg。
RBC 和 rs2231142 导致伊马替尼的药代动力学变异，基于患者特征的个体化剂量推荐可能是必要的。
