Population pharmacokinetics of imatinib and the role of α1-acid glycoprotein
Population pharmacokinetics of imatinib and the role of α1-acid glycoprotein
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DOI：
10.1111/j.1365-2125.2006.02719.x
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发表时间：
2006-07-01
影响因子：
3.4
通讯作者：
Buclin, T.
中科院分区：
文献类型：
--
作者：
Widmer, N.;Decosterd, L. A.;Buclin, T.
Aims-本观察性研究的目的是评估伊马替尼药代动力学的变异性，并探讨其处置和各种生物协变量之间的关系，特别是血浆α（1）-酸性糖蛋白concentrations.Methods进行群体药代动力学分析，使用NONMEM的基础上，从59例慢性粒细胞白血病或胃肠道间质瘤患者的321个血浆样本。检查协变量对口服清除率和分布容积的影响。结果一级吸收的一室模型适当地描述了数据，给出平均（+/- SEM）口服清除率为14.3 l h（-1）（+/- 1.0）和分布容积为347 l（+/- 62）。口服清除率受体重、年龄、性别和疾病诊断的影响。这些人口统计学协变量仍无法解释大部分个体间变异性（36%的清除率和63%的分布容积）。血浆α（1）-酸性糖蛋白浓度对伊马替尼总浓度有显著影响。此外，我们观察到一个内/外的比例为8，表明大量摄取的药物进入靶cells.Conclusions由于伊马替尼的高药代动力学变异性和其血浆浓度和疗效和毒性之间的关系，有用的治疗药物监测作为一种援助，以优化治疗，应进一步研究。理想情况下，这种方法应考虑循环α（1）-酸性糖蛋白浓度或游离伊马替尼浓度。
Aims The aims of this observational study were to assess the variability in imatinib pharmacokinetics and to explore the relationship between its disposition and various biological covariates, especially plasma alpha(1)-acid glycoprotein concentrations.Methods A population pharmacokinetic analysis was performed using NONMEM based on 321 plasma samples from 59 patients with either chronic myeloid leukaemia or gastrointestinal stromal tumours. The influence of covariates on oral clearance and volume of distribution was examined. Furthermore, the in vivo intracellular pharmacokinetics of imatinib was explored in five patients.Results A one-compartment model with first-order absorption appropriately described the data, giving a mean (+/- SEM) oral clearance of 14.3 l h(-1) (+/- 1.0) and a volume of distribution of 347 l (+/- 62). Oral clearance was influenced by body weight, age, sex and disease diagnosis. A large proportion of the interindividual variability (36% of clearance and 63% of volume of distribution) remained unexplained by these demographic covariates. Plasma alpha(1)-acid glycoprotein concentrations had a marked influence on total imatinib concentrations. Moreover, we observed an intra/extracellular ratio of 8, suggesting substantial uptake of the drug into the target cells.Conclusions Because of the high pharmacokinetic variability of imatinib and the reported relationships between its plasma concentration and efficacy and toxicity, the usefulness of therapeutic drug monitoring as an aid to optimizing therapy should be further investigated. Ideally, such an approach should take account of either circulating alpha(1)-acid glycoprotein concentrations or free imatinib concentrations.