Westfälische Wilhelms-Universität Münster, Institut für Pharmazeutische und Medizinische Chemie-Klinische Pharmazie, Corrensstraße 48, 48149, Münster, Germany.
Clinical Pharmacology Department, Hospital Universitario de la Princesa, Pharmacology Department, Faculty of Medicine, Universidad Autonoma de Madrid, Instituto de Investigación Sanitaria la Princesa (IIS-Princesa), Madrid, Spain.
Cancer Chemother Pharmacol. 2022 Aug;90(2):125-136. doi: 10.1007/s00280-022-04454-y. Epub 2022 Jul 14.
Imatinib is indicated for treatment of CML, GIST, etc. The population pharmacokinetics (popPK) of imatinib in patients under long-term treatment are reported in literature. Data obtained from bioequivalence trials for healthy subjects were used to evaluate the influence of demographic and pharmacogenetic factors on imatinib pharmacokinetics (PK) in a collective without concurrent drugs, organ dysfunction, inflammation etc. In addition, the differences in PK between the healthy subjects and a patient cohort was examined to identify possible disease effects.
26 volunteers were administered orally with single dose of 400 mg imatinib. 16-19 plasma samples per volunteer were collected from 0.5 up to 72 h post-dose. The popPK was built and post hoc estimates were compared with previously published PK parameters evaluated by non-compartmental analysis in the same cohort. The predictivity of the model for data collected from 40 patients with gastrointestinal stromal tumors at steady state was evaluated.
The popPK was best described by a two-compartment transit model with first-order elimination. No significant covariates were identified, probably due to the small cohort and the narrow range of demographic covariates; CYP3A5 phenotypes appeared to have some influence on the clearance of imatinib. Good agreement between non-compartment and popPK analyses was observed with the differences of the geometric means/ median of PK estimates below 10%. The model indicated lower clearance for patients compared to healthy volunteers (p value < 0.01).
The two-compartment transit model adequately describes the absorption and distribution of imatinib in healthy volunteers. For patients, a lower clearance of imatinib compared to healthy volunteer was estimated by the model. The model can be applied for dose individualization based on trough concentrations assuming no significant differences in absorption between patients and healthy volunteers.
伊马替尼适用于治疗 CML、GIST 等疾病。文献中报道了长期接受治疗的患者中伊马替尼的群体药代动力学（popPK）。使用来自健康受试者生物等效性试验的数据，评估人口统计学和遗传因素对无合并用药、器官功能障碍、炎症等情况下的伊马替尼药代动力学（PK）的影响。此外，还检查了健康受试者和患者队列之间 PK 的差异，以确定可能的疾病影响。
26 名志愿者单次口服 400mg 伊马替尼。从给药后 0.5 小时到 72 小时，每个志愿者采集 16-19 个血浆样本。构建 popPK 并与同一队列中非房室分析评估的先前发表的 PK 参数进行事后估计进行比较。评估该模型对 40 名胃肠道间质瘤患者稳态时数据的预测能力。
popPK 最好用具有一阶消除的两室转运模型来描述。由于队列较小且人口统计学协变量范围较窄，未发现有意义的协变量；CYP3A5 表型似乎对伊马替尼的清除有一定影响。非房室和 popPK 分析之间的一致性较好，PK 估计值的几何平均值/中位数的差异低于 10%。与健康志愿者相比，该模型表明患者的清除率较低（p 值<0.01）。
两室转运模型能较好地描述伊马替尼在健康志愿者中的吸收和分布。对于患者，该模型估计伊马替尼的清除率比健康志愿者低。假设患者和健康志愿者之间的吸收没有显著差异，该模型可用于基于谷浓度进行个体化剂量调整。
