Hu Pei, Chen Jia, Liu Dongyang, Zheng Xin, Zhao Qian, Jiang Ji
Clinical Pharmacology Research Center, Peking Union Medical College Hospital and Chinese Academy of Medical Sciences, Beijing, China,
Eur J Clin Pharmacol. 2015 Jul;71(7):843-50. doi: 10.1007/s00228-015-1864-5. Epub 2015 May 21.
Icotinib is a potent and selective inhibitor of epidermal growth factor receptors (EGFR) approved to treat non-small cell lung cancer (NSCLC). However, its high variability may impede its application. The objectives of this analysis were to assess plasma pharmacokinetics and identify covariates that may explain variability in icotinib absorption and/or disposition following single dose of icotinib in healthy volunteers.
Data from two clinical studies (n = 22) were analyzed. One study was designed as three-period and Latin-squared (six sequence) trial to evaluate dose proportionality, and the other one was designed as two-way crossover trial to evaluate food effect on pharmacokinetics (PK) characters. Icotinib concentrations in plasma were analyzed using non-linear mixed-effects model (NONMEM) method. The model was used to assess influence of food, demographic characteristics, measurements of blood biochemistry, and CYP2C19 genotype on PK characters of icotinib in humans. The final model was diagnosed by goodness-of-fit plots and evaluated by visual predictive check (VPC) and bootstrap methods.
A two-compartment model with saturated absorption character was developed to capture icotinib pharmacokinetics. Typical value of clearance, distribution clearance, central volume of distribution, maximum absorption rate were 29.5 L/h, 24.9 L/h, 18.5 L, 122.2 L and 204,245 μg/h, respectively. When icotinib was administrated with food, bioavailability was estimated to be increased by 48%. Inter-occasion variability was identified to affect on maximum absorption rate constant in food-effect study. CL was identified to be significantly influenced by age, albumin concentration (ALB), and CYP2C19 genotype. No obvious bias was found by VPC and bootstrap methods.
The developed model can capture icotinib pharmacokinetics well in healthy volunteers. Food intake can increase icotinib exposure. Three covariates, age, albumin concentration, and CYP2C19 genotype, were identified to significantly affect icotinib PK profiles in healthy subjects.
埃克替尼是一种强效、选择性的表皮生长因子受体（EGFR）抑制剂，已被批准用于治疗非小细胞肺癌（NSCLC）。然而，其高度变异性可能会阻碍其应用。本分析的目的是评估健康志愿者单次服用埃克替尼后的血浆药代动力学，并确定可能解释埃克替尼吸收和/或处置变异性的协变量。
分析了两项临床研究（n = 22）的数据。一项研究设计为三周期拉丁方（六个序列）试验以评估剂量比例性，另一项设计为双向交叉试验以评估食物对药代动力学（PK）特征的影响。采用非线性混合效应模型（NONMEM）方法分析血浆中埃克替尼的浓度。该模型用于评估食物、人口统计学特征、血液生化指标和CYP2C19基因型对人体埃克替尼PK特征的影响。通过拟合优度图对最终模型进行诊断，并通过可视化预测检查（VPC）和自助法进行评估。
建立了一个具有饱和吸收特征的二室模型来描述埃克替尼的药代动力学。清除率、分布清除率、中央分布容积、最大吸收率的典型值分别为29.5 L/h、24.9 L/h、18.5 L、122.2 L和204,245 μg/h。当埃克替尼与食物一起给药时，生物利用度估计增加48%。在食物效应研究中，发现给药间隔间变异性会影响最大吸收速率常数。清除率被确定受年龄、白蛋白浓度（ALB）和CYP2C19基因型的显著影响。VPC和自助法未发现明显偏差。
所建立的模型能够很好地描述健康志愿者体内埃克替尼的药代动力学。食物摄入可增加埃克替尼的暴露量。确定了年龄、白蛋白浓度和CYP2C19基因型这三个协变量会显著影响健康受试者的埃克替尼PK曲线。
