Кобиметиниб

Описание

Cobimetinib, codeveloped by Genentech and Exelixis, was approved in August 2015 in Switzerland and November 2015 in the U.S. and Europe for the treatment of unresectable or metastatic BRAFV600 mutationpositive melanoma when used in combination with vemurafenib. Cobimetinib is a potent, highly selective reversible inhibitor of mitogen-activated protein kinases (MEK) 1 and 2,120 which serves to inhibit phosphorylation of ERK1/2,121 disrupting the MAPK pathway which is responsible for cell proliferation, cell survival, and migration.122 Combination of cobimetinib with vemurafenib, an important BRAF inhibitor,123 enables targeting of multiple points on the MAPK pathway, leading to overall enhanced tumor cell apoptosis and response as compared to stand-alone treatment with vemurafenib.124 Specifically, in a representative trial of previously untreated patients with BRAFV600 mutation-positive, unresectable, stage IIIc or IV melanoma, combination of these two therapies led to a significantly improved progression-free survival and overall response rate versus patients treated only with vemurafenib.

Использование

A potent, selective, orally bioavailable inhibitor of MEK1, a component of the RAS/RAF/MEK/ERK pathway. It inhibits proliferation and stimulates apoptosis in a variety of human tumor cell lines. In preclinical xenograft models, oral administration of XL518 results in sustained inhibition of pERK in tumor tissue, but not brain tissue, leading to tumor growth inhibition and regression at well tolerated doses.

Имя бренда

Cotellic

Фармакокине?тика

Cobimetinib has only moderate oral bioavailability (46%), likely due to metabolism rather than incomplete absorption. However, it displays prolonged elimination half-life (44 h), which supports a once-daily dosing regimen (60 mg). Following oral administration, the unchanged cobimetinib and metabolite 4 were the major circulating components in the plasma up to 48 hours post dose (AUC0–48), accounting for 21% and 18% of all the circulating drug-related components, respectively (Fig. 4).

target

Primary target: MEK1/2