Department of Pharmaceutics, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing 100191, China.
Acta Pharmacol Sin. 2013 Nov;34(11):1427-36. doi: 10.1038/aps.2013.101. Epub 2013 Oct 7.
Erlotinib is used to treat non-small-cell lung cancer (NSCLC), which targets epidermal growth factor receptor (EGFR) tyrosine kinase. The aim of this study was to investigate the relationship between erlotinib plasma concentrations and phosphorylated EGFR (pEGFR) levels, as well as the relationship between pEGFR levels and tumor growth inhibition in a human non-small-cell lung cancer xenograft mouse model.
Female BALB/c nude mice were implanted with the human NSCLC cell line SPC-A-1. The animals were given via gavage a single dose of erlotinib (4, 12.5, or 50 mg/kg). Pharmacokinetics of erlotinib was determined using LC-MS/MS. Tumor volume and pEGFR levels in tumor tissues were measured at different time points after erlotinib administration. The levels of pEGFR in tumor tissues was detected using Western blotting and ELISA assays.
The pharmacokinetics of erlotinib was described by a two-compartment model with first order extravascular absorption kinetics. There was a time delay of approximately 2 h between erlotinib plasma concentrations and pEGFR degradation. The time course of pEGFR degradation was reasonably fit by the indirect response model with a calculated IC50 value of 1.80 μg/mL. The relationship between pEGFR levels and tumor volume was characterized by the integrated model with a Kbio value of 0.507 cm(3)/week, which described the impact of pEGFR degradation on tumor growth.
The pharmacokinetic/pharmacodynamic properties of erlotinib in a human tumor xenograft model were described by the indirect response model and integrated model, which will be helpful in understanding the detailed processes of erlotinib activity and determining an appropriate dosing regimen in clinical studies.
厄洛替尼用于治疗非小细胞肺癌（NSCLC），其作用靶点是表皮生长因子受体（EGFR）酪氨酸激酶。本研究旨在探讨厄洛替尼血药浓度与磷酸化 EGFR（pEGFR）水平之间的关系，以及在人非小细胞肺癌异种移植小鼠模型中 pEGFR 水平与肿瘤生长抑制之间的关系。
将人 NSCLC 细胞系 SPC-A-1 植入雌性 BALB/c 裸鼠。通过灌胃给予动物单次厄洛替尼（4、12.5 或 50mg/kg）。采用 LC-MS/MS 法测定厄洛替尼的药代动力学。在厄洛替尼给药后不同时间点测量肿瘤体积和肿瘤组织中 pEGFR 水平。采用 Western blot 和 ELISA 法检测肿瘤组织中 pEGFR 水平。
厄洛替尼的药代动力学采用具有一级血管外吸收动力学的两室模型描述。厄洛替尼血浆浓度与 pEGFR 降解之间存在约 2 小时的时间延迟。pEGFR 降解的时程通过间接反应模型得到合理拟合，计算得出的 IC50 值为 1.80μg/mL。pEGFR 水平与肿瘤体积之间的关系采用整合模型来描述，其 Kbio 值为 0.507cm3/周，该模型描述了 pEGFR 降解对肿瘤生长的影响。
在人肿瘤异种移植模型中，厄洛替尼的药代动力学/药效学特性采用间接反应模型和整合模型来描述，这将有助于深入了解厄洛替尼活性的详细过程，并在临床研究中确定合适的给药方案。
