EA4553, Institut Claudius Regaud et Université de Toulouse, France.
Clin Cancer Res. 2011 Jul 15;17(14):4862-71. doi: 10.1158/1078-0432.CCR-10-3278. Epub 2011 Jun 8.
The aim of this pharmacokinetic-pharmacodynamic (PK-PD) analysis was to evaluate the pharmacologic characteristics of erlotinib and its main metabolite (OSI-420) in pediatric patients compared with those in adult patients.
Plasma concentrations of erlotinib and OSI-420 of 46 children with malignant brain tumors included in a phase I study and 42 adults with head and neck carcinoma were analyzed by a population-pharmacokinetic method (NONMEM). The effect of several covariates and single nucleotide polymorphisms (SNP) in ABCB1, ABCG2, and CYP3A5 on pharmacokinetic parameters was evaluated. PK/PD relationships between plasma drug exposure Area Under the Curve (AUC) at day 1 and skin toxicity were studied in children and compared with the relationship observed in adults.
A significant difference in erlotinib clearance (P = 0.0001), when expressed in L·h(-1)·kg(-1), was observed between children and adults with mean values of 0.146 and 0.095, respectively (mean difference = 0.051 L·h(-1)·kg(-1), SD = 0.0594). However, a common covariate model was obtained describing erlotinib clearance according to body weight, alanine aminotransferase, ABCB1, and CYP3A5 polymorphisms (2677G > T/A and 6986G > A) for both children and adult patients. The PK-PD relationship was very consistent between the children and adult groups with risk of skin toxicity rising with increasing erlotinib AUC.
The nonlinear population approach applied to pharmacokinetic data combined with a pharmacokinetic-pharmacodynamic analysis revealed that the higher recommended dose in children (125 mg/m(2)/day) compared with adults (90 mg/m(2)/day) is mainly due to pharmacokinetic rather than pharmacodynamic particularities.
本药代动力学-药效学（PK-PD）分析旨在评估与成人患者相比，儿童恶性脑肿瘤患者中厄洛替尼及其主要代谢物（OSI-420）的药效学特征。
采用群体药代动力学方法（NONMEM）分析了一项 I 期研究中 46 例儿童恶性脑肿瘤患者和 42 例头颈部癌患者的厄洛替尼和 OSI-420 血浆浓度。评估了多种协变量和 ABCB1、ABCG2 和 CYP3A5 中的单核苷酸多态性（SNP）对药代动力学参数的影响。研究了儿童患者中第 1 天血浆药物暴露 AUC 与皮肤毒性之间的 PK/PD 关系，并与成人患者的关系进行了比较。
与成人相比，儿童患者的厄洛替尼清除率（CL/F）差异有统计学意义（P=0.0001），分别为 0.146 L·h-1·kg-1和 0.095 L·h-1·kg-1（平均差异=0.051 L·h-1·kg-1，SD=0.0594）。然而，根据体重、丙氨酸氨基转移酶、ABCB1 和 CYP3A5 多态性（2677G>T/A 和 6986G>A），可以获得一个描述儿童和成人患者厄洛替尼 CL/F 的共同协变量模型。儿童和成人组的 PK-PD 关系非常一致，皮肤毒性的风险随厄洛替尼 AUC 的增加而升高。
应用于药代动力学数据的非线性群体方法结合药代动力学-药效学分析表明，与成人相比，儿童（125mg/m2/天）推荐剂量较高主要是由于药代动力学而不是药效学的特殊性。
