Association of pharmacokinetics or pharmacogenomics with toxicity of erlotinib in patients with advanced non-small cell lung cancer

口服厄洛替尼的药代动力学表现出较大的个体间差异。本研究的目的是评价厄洛替尼在晚期NSCLC患者中的药代动力学或药物基因组学与毒性的相关性。采用高效液相色谱法分析厄洛替尼的血浆浓度。直接测序分析ABCG 2、ABCB 1、ABCC 2、CYP3A4、CYP3A5、CYP1A1和CYP1A2基因型，厄洛替尼的皮肤毒性、腹泻、口腔炎、肝损伤和间质性肺疾病（ILD）等毒性与药代动力学或药物基因组学无统计学显著相关性。然而，1例患者死于药物诱导的ILD，其为ABCG 2 C>A纯合子，并显示出最高的AUC。此外，4例肝损伤患者的Cmax有高于无肝损伤患者的趋势（p=0.054）。总之，ABCG 2 C>A纯合子可能与厄洛替尼暴露量升高和药物诱导的ILD相关。

The orally administered erlotinib showed large interindividual variability in its pharmacokinetics. The aim of this study was to evaluate the association of pharmacokinetics or pharmacogenomics with toxicity of erlotinib in patients with advanced NSCLC. Plasma concentration of erlotinib was analyzed by high-performance liquid chromatography. The genotypes of ABCG2, ABCB1, ABCC2, CYP3A4, CYP3A5, CYP1A1, and CYP1A2 were analyzed by direct sequencing.There were no statistically significant association of pharmacokinetics or pharmacogenomics with toxicity, such as skin toxicity, diarrhea, stomatitis, liver injury, and interstitial lung disease (ILD) of erlotinib. However, one patient died of drug induced ILD was homozygous for ABCG2 C>A and showed the highest AUC. Additionally, Cmax was trend toward to higher in 4 patients with liver injury than those without (p=0.054). In conclusion, the homozygote of ABCG2 C>A could be associated with elevated erlotinib exposure and drug-induced ILD.