title: Efficacy of afatinib, an irreversible ErbB family blocker, in the treatment of intracerebral metastases of non-small cell lung cancer in mice.
abstract: Few effective therapeutic options are currently available for the treatment of non-small cell lung cancer (NSCLC) with brain metastases (BM). Recent evidence shows that NSCLC patients with BMs respond well to afatinib, but little is known about the underlying mechanisms. In this study, we evaluated the efficacy of afatinib in treatment of BMs in mice and investigated whether afatinib could actively penetrate the brain-blood barrier and bind to its target. NSCLC BM model was established in nude mice by intracerebral injection of PC-9.luc cells. The tumors were measured weekly using in vivo quantitative bioluminescence. The mice are administrated afatinib (15, 30 mg·kg-1·d-1, ig) for 14 d. The antitumor efficacy of afatinib was determined by tumor growth inhibition (TGI), which was calculated as [1-(change of tumor volume in treatment group/control group)×100]. Pharmacokinetic characteristics were measure in mice receiving a single dose of afatinib (30 mg/kg, ig). Pharmacodynamics of afatinib was also assessed by detecting the expression of pEGFR (Tyr1068) in brain tumor foci using immunohistochemistry. Administration of afatinib (15, 30 mg·kg-1·d-1) dose-dependently inhibited PC-9 tumor growth in the brain with a TGI of 90.2% and 105%, respectively, on d 14. After administration of afatinib (30 mg/kg), the plasma concentration of afatinib was 91.4±31.2 nmol/L at 0.5 h, reached a peak (417.1±119.9 nmol/L) at 1 h, and was still detected after 24 h. The cerebrospinal fluid (CSF) concentrations followed a similar pattern. The T1/2values of afatinib in plasma and CSF were 5.0 and 3.7 h, respectively. The AUC(0-24 h)values for plasma and CSF were 2375.5 and 29.1 nmol/h, respectively. The plasma and CSF concentrations were correlated (r=0.844, P<0.01). Pharmacodynamics study showed that the expression levels of pEGFR were reduced by 90% 1 h after afatinib administration. The Emaxwas 86.5%, and the EC50was 0.26 nmol/L. A positive correlation between CSF concentrations and pEGFR modulation was revealed. Afatinib penetrates the BBB in NSCLC BM mice and contributes to the brain tumor response. The CSF exposure level is correlated with the plasma level, which in turn is correlated with the modulation of pEGFR in the tumor tissues. The results support for the potential application of afatinib in NSCLC patients with BMs.
authors.affiliation: Hangzhou Translational Medicine Research Center, Hangzhou First People's Hospital, Nanjing Medical University, Hangzhou 310006, China.|Hangzhou Translational Medicine Research Center, Affiliated Hangzhou First People's Hospital of Zhejiang Chinese Medical University, Hangzhou 310006, China.
authors.forename: Shi-Rong
authors.initials: SR
authors.lastname: Zhang
authors.affiliation: Hangzhou Translational Medicine Research Center, Hangzhou First People's Hospital, Nanjing Medical University, Hangzhou 310006, China.|Department of Oncology, Hangzhou Cancer Hospital, Hangzhou 310006, China.
authors.forename: Lu-Cheng
authors.initials: LC
authors.lastname: Zhu
authors.affiliation: Hangzhou Translational Medicine Research Center, Hangzhou First People's Hospital, Nanjing Medical University, Hangzhou 310006, China.
authors.forename: Yan-Ping
authors.initials: YP
authors.lastname: Jiang
authors.affiliation: Hangzhou Translational Medicine Research Center, Hangzhou First People's Hospital, Nanjing Medical University, Hangzhou 310006, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Pathology, Hangzhou First People's Hospital, Nanjing Medical University, Hangzhou 310006, China.
authors.forename: Ru-Jun
authors.initials: RJ
authors.lastname: Xu
authors.affiliation: Hangzhou Translational Medicine Research Center, Hangzhou First People's Hospital, Nanjing Medical University, Hangzhou 310006, China.|Hangzhou Translational Medicine Research Center, Affiliated Hangzhou First People's Hospital of Zhejiang Chinese Medical University, Hangzhou 310006, China.
authors.forename: Ya-Si
authors.initials: YS
authors.lastname: Xu
authors.affiliation: Department of Oncology, Hangzhou Cancer Hospital, Hangzhou 310006, China.
authors.forename: Bing
authors.initials: B
authors.lastname: Xia
authors.affiliation: Hangzhou Translational Medicine Research Center, Hangzhou First People's Hospital, Nanjing Medical University, Hangzhou 310006, China.|Hangzhou Translational Medicine Research Center, Affiliated Hangzhou First People's Hospital of Zhejiang Chinese Medical University, Hangzhou 310006, China.|Department of Oncology, Hangzhou First People's Hospital, Nanjing Medical University, Hangzhou 310006, China.
authors.forename: Sheng-Lin
authors.initials: SL
authors.lastname: Ma
mesh_terms: D000077716:Afatinib; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000556:secondary*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000473:pathology*; D045744:Cell Line, Tumor; D002555:Cerebrospinal Fluid / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D066246:ErbB Receptors / Q000378:metabolism*; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000473:pathology*; D051379:Mice; D008819:Mice, Nude; D010766:Phosphorylation / Q000187:drug effects; D011799:Quinazolines / Q000097:blood / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D011799:Quinazolines; D000077716:Afatinib; D066246:ErbB Receptors