MEK1/2抑制剂曲美替尼的药理作用与临床评价

Pharmacology and clinical evaluation of trametinib,a reversible inhibitor of MEK1/2

曲美替尼是一种丝裂原活化细胞外信号调节激酶1/2可逆性抑制剂,主要通过对MEK蛋白(胞外信号相关激酶(ERK)通路的上游调节器)的作用,影响MAPK通路,抑制细胞增殖;在体内、体外均可抑制BRAF V600突变阳性的黑色素瘤细胞的生长。美国FDA于2013年5月批准其用于治疗BRAF V600E或V600K基因突变的不可切除或转移性黑色素瘤。本品在早期的试验中显示了很好的临床疗效,特别是对于BRAF V600突变的黑色素瘤,在近期的III期临床研究中,相比于其他细胞毒的化疗药物,显示了无进展生存期和总生存期更长的优势。本文以曲美替尼为关键词进行文献检索,并对其作用机制、药动学、临床评价,剂量及安全性等进行综述。

Trametinib, a reversible inhibitor of mitogen-activated extracellular signal-regulated kinase 1 （ MEK1 ） and MEK2, can influence the MAPK pathway and inhibit the cellular proliferation by activation of MEK1 and MEK2 kinases, which are upstream regulators of the extracellular signal-related kinase （ERK） pathway. Trametinib inhibis BRAF V600 mutation-positive melanoma cell growth both in vitro and in vivo, and its treatment on the BRAF V600E or V600K mutation-positive melanoma have been approved by FDA on May 2013. In early stage clinical trials, trametinib showed good efficacies, especially for the treatment of BRAF V600 mutation-positive melanoma. Recently in a phase Ⅲ clinical trial, trametinib demonstrated significant increase in progression-free survival and overall survival in the patients compared to other chemotherapy drugs. A literature search was conducted with key words trametinib. The pharmacology, pharmacokinetics, clinical research, dosage and safety were reviewed in this paper.