生物活性

• 靶点

  EGFR (L858R) IC50:0.4nM

  EGFR IC50:0.5nM

  EGFR (T790M, L858R) IC50:10nM

  HER2 IC50:14nM

• 描述EGFR (epidermal growth factor receptor) family consists of four members that belong to the ErbB lineage of proteins (ErbB1–4) with an external domain that binds activating ligands, such as EGF, and is overexpressed in a significant percentage of carcinomas and contributes to the malignant phenotype. Upon activation, EGFR phosphorylates both the receptor itself and a variety of “effector” protein. Afatinib Dimaleate is the dimaleate form of Afatinib. Afatinib is an irreversible inhibitor of pan-ErbB inhibitor with IC50 values of 0.4nM, 0.5nM, 10nM, 14nM and 1nM for EGFR (L858R), EGFR (wt), EGFR (L858R/T790M), HER2 (measured by cell-free in vitro kinase assays) and ErbB4, respectively. Afatinib displays potent cellular effects on both EGFR and HER2 phosphorylation in cell lines with the in vitro kinase results, as well as anchorage-independent proliferation in NIH-3T3 cells ectopically expressing EGFR mutants. Afatinib inhibited survival of human NSCLC cell lines expressing HER2 776insV (NCI-H1781) or EGFR E746_A750del (HCC827), but showed no activity toward A549 cells, which expressed wild-type EGFR and HER2, but simultaneously harboring an oncogenic Kras G12S point mutation. Daily oral treatment with Afatinib at dose of 20mg/kg for 25 days resulted in dramatic tumor regression and downregulation of EGFR and AKT phosphorylation in A431 cells xenografted models. Also the tumor regression by Afatinib can be observed in NCI-N87 cells and H1975 cells xenografted animals.

• 动物研究
  剂量	Rat: 4 mg/kg[3] (i.v.); 8 mg/kg[3] (p.o.)
  给药途径	i.v., p.o.
  动物药代数据	Animal Rats[3] Dose 4 mg/kg (i.v.) 8 mg/kg (p.o.) Administration i.v. p.o. MRT 4.95 h (i.v.) 6.65 h (p.o.) AUC0→24h 2500 nmol·h/l (i.v.) 2540 nmol·h/l (p.o.) T1/2 5.22 h (i.v.) 4.54 h (p.o.) Tmax 4 h (p.o.) Vz/F 25.0 L/kg (i.v.) 42.8 L/kg (p.o.) Cmax 1620 nmol/l (i.v.) 397 nmol/l (p.o.) AUC0→∞ 2920 nmol·h/l (i.v.) 2600 nmol·h/l (p.o.) Vss/F 16.2 L/kg (i.v.) 43.6 L/kg (p.o.) CL/F 55.3 ml/min·kg (i.v.) 108 ml/min·kg (p.o.)

• 临床研究

• NCT号	适应症或疾病	临床期	招募状态	预计完成时间	地点
  NCT01649271	Breast Neoplasms ... more >> Stomach Neoplasms Collapse <<	Phase 1	Completed	-	France ... more >> CTR Georges-François Leclerc Dijon, France, 21079 CTR René Gauducheau, Onco, St Herblain Saint Herblain Cedex, France, 44805 INS Claudius Regaud Toulouse, France, 31059 Collapse <<
  NCT01251653	-	-	Completed	-	France ... more >> 1200.93.33002 Boehringer Ingelheim Investigational Site Dijon, France 1200.93.33001 Boehringer Ingelheim Investigational Site Saint-Herblain cedex, France 1200.93.33003 Boehringer Ingelheim Investigational Site Toulouse, France Collapse <<
  NCT03157089	Carcinoma, Non-Small-Cell Lung	Phase 2	Recruiting	October 9, 2020	United States, California ... more >> University of California Davis Recruiting Sacramento, California, United States, 95817 Contact: Jonathan Riess    +001 (916) 734-3772    jwriess@ucdavis.edu    United States, District of Columbia Johns Hopkins Sidney Kimmel Cancer Center at Sibley Memorial Hospital Recruiting Washington, District of Columbia, United States, 20016 Contact: Benjamin Levy    +001 (202) 660-6500    blevy11@jhmi.edu    United States, Florida Florida Hospital Recruiting Orlando, Florida, United States, 32804 Contact: Tarek Mekhail    +001 (407) 303-3235    tarek.mekhail.md@flhosp.org    United States, Kentucky Baptist Health Medical Group Recruiting Lexington, Kentucky, United States, 40503 Contact: Firas Badin    +001 (859) 276-0414    firas.badin@bhsi.com    United States, Nevada Comprehensive Cancer Centers of Nevada Recruiting Las Vegas, Nevada, United States, 89128 Contact: Brian Vicuna    +001 (702) 952-2140    brian.vicuna@usoncology.com    United States, New York Weill Cornell Medical College Recruiting New York, New York, United States, 10021 Contact: Ronald Scheff    +001 (646) 962-2066    rjs2002@med.cornell.edu    United States, Washington Cancer Care Northwest Centers, PS Recruiting Spokane Valley, Washington, United States, 99216 Contact: Srivalli Gopaluni    +001 (509) 228-1000    srivalli.gopaluni@ccnw.net    France HOP Côte de Nacre Recruiting Caen, France, 14033 Contact: Jeannick Madelaine    +33 (0)2 31 06 46 76    Madelaine-j@chu-caen.fr    HOP Le Mans Recruiting Le Mans, France, 72037 Contact: Olivier Molinier    +33 (0)2 43 43 24 50    omolinier@ch-lemans.fr    HOP Nord Recruiting Marseille, France, 13015 Contact: Fabrice Barlesi    +33 (0)4 91 38 56 28    fabrice.barlesi@ap-hm.fr    HOP Nord Laënnec Recruiting Nantes, France, 44093 Contact: Jaafar Bennouna    +33 (0)2 40 67 99 93    Jaafar.Bennouna@univ-nantes.fr    HOP Sainte Musse Recruiting Toulon, France, 83100 Contact: Clarisse Audigier-Valette    +33 (0)4 94 14 56 10    clarisse.audigier-valette@ch-toulon.fr    Korea, Republic of Severance Hospital Recruiting Seoul, Korea, Republic of, 03722 Contact: Hye Ryun Kim    82 2 2228 8125    nobelg@yuhs.ac    Asan Medical Center Recruiting Seoul, Korea, Republic of, 05505 Contact: Sang-We Kim    82 2 3010 3215    swkim@amc.seoul.kr    Spain Hospital Vall d'Hebron Recruiting Barcelona, Spain, 08035 Contact: Enriqueta Felip    +34932746077    efelip@vhio.net    Complejo Hospitalario Universitario Insular - Materno Infantil Recruiting Las Palmas de Gran Canaria, Spain, 35016 Contact: Delvys Rodríguez Abreu    +34928441738    drodabr@gobiernodecanarias.org    Hospital Universitario 12 de Octubre Recruiting Madrid, Spain, 28041 Contact: Luis Paz-Ares Rodríguez    +34913908349    lpazaresr@seom.org    Hospital Clínico Universitario Lozano Blesa Recruiting Zaragoza, Spain, 50009 Contact: Dolores Isla    +34976765746    lola.isla@gmail.com    Turkey Hacettepe Universitesi Tip Fakultesi, Onkoloji ABD Active, not recruiting Ankara, Turkey, 06230 Istanbul Universitesi Cerrahpasa Tip Fakultesi Completed Istanbul, Turkey, 34098 Collapse <<

• 更多
• 参考文献

• [1] Wang XK, He JH, et al. Afatinib enhances the efficacy of conventional chemotherapeutic agents by eradicating cancer stem-like cells. Cancer Res. 2014 Aug 15;74(16):4431-45.

  [2] Li D, Ambrogio L, et al. BIBW2992, an irreversible EGFR/HER2 inhibitor highly effective in preclinical lung cancer models. Oncogene. 2008 Aug 7;27(34):4702-11.

  [3] Afatinib Dimaleate