生物活性

• 靶点

  VEGFR3 IC50:5.2nM

  VEGFR2 IC50:4nM

• 描述SCF is abundantly expressed in a broad spectrum of human malignancies, such asSCLC, NSCLC, colon, breast and renal cancers, acting through both activation of its receptor KIT and paracrine angiogenesis factor. Lenvatinib is a multiple receptor tyrosine kinases inhibitor with IC50 values of 4.0nM, 5.2nM, 22nM, 39nM, 46nM, 51nM and 100nM for VEGFR2, VEGFR3, VEGFR1, PDGFRβ, FGFR1, PDGFRα and Kit (measured by HTRF assays), respectively. Exposure to Lenvatinib inhibited SCF-induced KIT (Tyr719) phosphorylation and VEGF-induced KDR (Tyr996) phosphorylation in HUVEC with IC50 values of 1.9nM and 0.83nM. Consistent with its inhibition of this two targets, the sandwich tube formation (sTF) assay showed that treatment with Lenvatinib inhibited either VEGF or SCF-induced tube formation of HUVEC in a dose-dependent manner with IC50s of 5.2 and 5.1nM, respectively. Though Lenvatinib did not show the potent inhibitory activities against H146 cells expressing SCF, but not KIT, it inhibited SCF-induced cell proliferation of human SCLC, H526 cells expressing KIT, suggesting the inhibition by Lenvatinib on cell growth through paracrine. Oral administration of Lenvatinib at dose of 30 and 100 mg/kg (BID, QDx21) caused tumor growth in a dose-dependent manner in H146 xenograft, while tumor regression achieved at dose of 100mg/kg with decreased microvessel density^[1].

• 动物研究
  剂量	Mice: 3 mg/kg - 100 mg/kg[1] (p.o.)
  给药途径	p.o.
  动物药代数据	Animal Mice[2] Rats[2] Dogs[2] Monkeys[2] Dose 3 mg/kg 3 mg/kg 3 mg/kg 3 mg/kg Administration i.v. or p.o. i.v. or p.o. i.v. or p.o. i.v. or p.o. F 64.4% (p.o.) 68.7% (p.o.) 70.4% (p.o.) 78.4% (p.o.) AUC0→inf 8.686 μg·h/ml (i.v.) 5.596 μg·h/ml (p.o.) 8.417 μg·h/ml (i.v.) 5.481 μg·h/ml (p.o.) 12.900 μg·h/ml (i.v.) 10.272 μg·h/ml (p.o.) T1/2 2.05 h (i.v.) 2.09 h (p.o.) 3.65 h (i.v.) 3.61 h (p.o.) 5.27 h (i.v.) 4.76 h (p.o.) 4.28 h (i.v.) 4.07 h (p.o.) Tmax 0.5 h (p.o.) 0.5 h (p.o.) 2 h (p.o.) 2 h (p.o.) CLp 345.4 ml/h/kg (i.v.) 100.2 ml/h/kg (i.v.) 368.3 ml/h/kg (i.v.) 237.7 ml/h/kg (i.v.) AUC0-inf 30.107 μg·h/ml (i.v.) 20.697 μg·h/ml (p.o.) Cmax 7.0542 μg/ml (i.v.) 1.9651 μg/ml (p.o.) 14.0567 μg/ml (i.v.) 6.1671 μg/ml (p.o.) 2.2889 μg/ml (i.v.) 1.2717 μg/ml (p.o.) 4.6427 μg/ml (i.v.) 2.5013 μg/ml (p.o.) Vss 714.3 ml/kg (i.v.) 391.5 ml/kg (i.v.) 1610.0 ml/kg (i.v.) 793.7 ml/kg (i.v.)

• 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
  NCT03413176	-	-	Completed	-	France ... more >> AP-HP, Pitié-Salpêtrière Hospital, Department of Pharmacology, CIC-1421, Pharmacovigilance Unit, INSERM. Paris, France, 75013 Collapse <<
  NCT03499626	Advanced/ Metastatic Hepatocel... more >>lular Carcinoma Collapse <<	Phase 1 Phase 2	Recruiting	May 5, 2021	Singapore ... more >> National University Hospital Recruiting Singapore, Singapore, 119228 Contact: Raghav Sundar    (65) 6779 5555    raghav_sundar@nuhs.edu.sg Collapse <<
  NCT03048877	Differentiated Thyroid Cancer	Phase 3	Recruiting	December 2019	China, Jiangsu ... more >> Nanjing PLA 81 Hospital Recruiting Nanjing, Jiangsu, China Contact: Shukui Qin, Prof. M.D.    +86-26-84453932    qinsk@csco.org.cn    China Peking Union Medical College Hospital Recruiting Peking, China, 100730 Contact: Lin Yansong, MD    +86-10-69155610    linys@pumch.cn Collapse <<

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• 参考文献

• [1] Tohyama O, Matsui J, et al. Antitumor activity of lenvatinib (e7080): an angiogenesis inhibitor that targets multiple receptor tyrosine kinases in preclinical human thyroid cancer models. J Thyroid Res. 2014;2014:638747.

  [2] Lenvatinib