Division of Clinical Pharmacology, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland.
Br J Clin Pharmacol. 2013 Apr;75(4):1007-18. doi: 10.1111/j.1365-2125.2012.04422.x.
Total imatinib concentrations are currently measured for the therapeutic drug monitoring of imatinib, whereas only free drug equilibrates with cells for pharmacological action. Due to technical and cost limitations, routine measurement of free concentrations is generally not performed. In this study, free and total imatinib concentrations were measured to establish a model allowing the confident prediction of imatinib free concentrations based on total concentrations and plasma proteins measurements.
One hundred and fifty total and free plasma concentrations of imatinib were measured in 49 patients with gastrointestinal stromal tumours. A population pharmacokinetic model was built up to characterize mean total and free concentrations with inter-patient and intrapatient variability, while taking into account α1 -acid glycoprotein (AGP) and human serum albumin (HSA) concentrations, in addition to other demographic and environmental covariates.
A one compartment model with first order absorption was used to characterize total and free imatinib concentrations. Only AGP influenced imatinib total clearance. Imatinib free concentrations were best predicted using a non-linear binding model to AGP, with a dissociation constant Kd of 319 ng ml(-1) , assuming a 1:1 molar binding ratio. The addition of HSA in the equation did not improve the prediction of imatinib unbound concentrations.
Although free concentration monitoring is probably more appropriate than total concentrations, it requires an additional ultrafiltration step and sensitive analytical technology, not always available in clinical laboratories. The model proposed might represent a convenient approach to estimate imatinib free concentrations. However, therapeutic ranges for free imatinib concentrations remain to be established before it enters into routine practice.
目前，伊马替尼的治疗药物监测是测量总伊马替尼浓度，而只有游离药物才能与细胞达到药理平衡。由于技术和成本的限制，通常不会常规测量游离浓度。在这项研究中，测量了游离和总伊马替尼浓度，以建立一个模型，允许基于总浓度和血浆蛋白测量值，对伊马替尼游离浓度进行有信心的预测。
在 49 名胃肠道间质瘤患者中测量了 150 个总伊马替尼和游离伊马替尼的血浆浓度。建立了群体药代动力学模型，以描述个体间和个体内的平均总浓度和游离浓度的变异性，同时考虑到 α1-酸性糖蛋白（AGP）和人血清白蛋白（HSA）的浓度，以及其他人口统计学和环境协变量。
采用具有一级吸收的单室模型来描述总伊马替尼和游离伊马替尼浓度。只有 AGP 影响伊马替尼的总清除率。使用非线性结合模型来预测 AGP 结合的伊马替尼游离浓度，解离常数 Kd 为 319ng/ml，假设结合比为 1:1，是预测伊马替尼游离浓度的最佳方法。在方程中加入 HSA 并不能改善伊马替尼未结合浓度的预测。
虽然游离浓度监测可能比总浓度更合适，但它需要额外的超滤步骤和敏感的分析技术，而这些技术在临床实验室中并不总是可用。所提出的模型可能是一种估计伊马替尼游离浓度的便捷方法。然而，在游离伊马替尼浓度进入常规实践之前，仍需要建立治疗范围。
