|Pharmacokinetic-pharmacodynamic modeling of the anticancer effect of erlotinib in a human non-small cell lung cancer xenograft mouse model|
|Wu, Qiong2; Li, Meng-yao2; Li, Han-qing2; Deng, Chen-hui2; Li, Liang1,2; Zhou, Tian-yan1,2; Lu, Wei1,2|
|关键词||Non-small-cell Lung Cancer Anticancer Drug Erlotinib Epidermal Growth Factor Receptor Pharmacokinetic-pharmacodynamic Modeling Human Tumor Xenograft Mouse Model|
|刊名||ACTA PHARMACOLOGICA SINICA|
|WOS标题词||Science & Technology|
|类目[WOS]||Chemistry, Multidisciplinary ; Pharmacology & Pharmacy|
|研究领域[WOS]||Chemistry ; Pharmacology & Pharmacy|
|关键词[WOS]||GROWTH-FACTOR RECEPTOR ; TYROSINE KINASE INHIBITOR ; BIOMARKER RESPONSE ; CARCINOMA ; MALIGNANCIES ; EXPRESSION ; PREDICTION ; THERAPY ; TARGET ; HEAD|
Aim: 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.
Methods: 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.
Results: 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 mu g/mL. The relationship between pEGFR levels and tumor volume was characterized by the integrated model with a K-bio value of 0.507 cm(3)/week, which described the impact of pEGFR degradation on tumor growth.
Conclusion: 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.
|项目编号||BMU20110263E ; 81273583|
|资助机构||Innovation Team of Ministry of Education ; National Natural Science Foundation of China|
|作者单位||1.Peking Univ, State Key Lab Nat & Biomimet Drugs, Beijing 100191, Peoples R China|
2.Peking Univ, Hlth Sci Ctr, Sch Pharmaceut Sci, Dept Pharmaceut, Beijing 100191, Peoples R China
|Wu, Qiong,Li, Meng-yao,Li, Han-qing,et al. Pharmacokinetic-pharmacodynamic modeling of the anticancer effect of erlotinib in a human non-small cell lung cancer xenograft mouse model[J]. ACTA PHARMACOLOGICA SINICA,2013,34(11):1427-1436.|
|APA||Wu, Qiong.,Li, Meng-yao.,Li, Han-qing.,Deng, Chen-hui.,Li, Liang.,...&Lu, Wei.(2013).Pharmacokinetic-pharmacodynamic modeling of the anticancer effect of erlotinib in a human non-small cell lung cancer xenograft mouse model.ACTA PHARMACOLOGICA SINICA,34(11),1427-1436.|
|MLA||Wu, Qiong,et al."Pharmacokinetic-pharmacodynamic modeling of the anticancer effect of erlotinib in a human non-small cell lung cancer xenograft mouse model".ACTA PHARMACOLOGICA SINICA 34.11(2013):1427-1436.|