セルメチニブ

Breast Feeding; Lactation; Milk, Human; Antineoplastic Agents; Enzyme Inhibitors; Protein Kinase Inhibitors; Tyrosine Kinase Inhibitors; Signal Transduction Inhibitors; MEK Inhibitors

FDA approved drugs -> Active ingredient

EMA approved medicines: Human medicine (Orphan designations)

Danger

H302 (40%): Harmful if swallowed [Warning Acute toxicity, oral]

P203, P260, P261, P264, P264+P265, P270, P272, P273, P280, P301+P317, P302+P352, P305+P354+P338, P317, P318, P319, P321, P330, P333+P317, P362+P364, P391, P405, and P501 (click each P-code to see the statement)

Aggregated GHS information provided per 5 reports by companies from 3 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

In the prelicensure clinical trials conducted in children and adults with neurofibromatosis, serum aminotransferase elevations occurred in 35% of treated subject but rose to above 5 times the upper limit of normal (ULN) in only 4%. However, there were no liver related serious adverse events and no patient had a concurrent elevation in serum aminotransferase and bilirubin levels. The ALT elevations were typically mild and transient and usually resolved even without dose adjustment. There were no instances of clinically apparent liver injury attributed to selumetinib. Since approval and more wide scale availability of selumetinib, there have been no published reports of clinically apparent drug induced liver injury associated with its use in neurofibromatosis, although clinical experience with the drug, particularly with long term therapy, has been limited. However, in studies of experimental therapy with somewhat higher doses of selumetinib in patients with advanced, refractory cancers, liver test abnormalities were common and sometimes graded as severe (ALT above 20 times ULN) and requiring drug discontinuation. Thus, in patients with neurofibromatosis and use of recommended doses of selumetinib, clinically apparent liver injury is rare if it occurs at all. At higher doses, however, selumetinib has been associated with a very high rate of serum enzyme elevations, many of which were in the range suggestive of severe injury.

L - Antineoplastic and immunomodulating agents

QL - Antineoplastic and immunomodulating agents

Selumetinib is a non-ATP-competitive mitogen-activated protein kinase kinase 1 and 2 (MEK1 and MEK2) inhibitor. By selectively targeting MEK1 and MEK2, selumetinib is able to inhibit oncogenic downstream effects of the Raf-MEK-ERK signaling pathway, which is often overactive in certain types of cancer. Indeed, a study investigating the effects of selumetinib in children with NF-1 found that treatment with the anti-neoplastic resulted in reduced tumor size. Decreases in tumor-associated pain and improvements in overall function were also subjectively reported. Selumetinib has minimal off-target activity, contributing to its impressive safety profile.

The Ras-Raf-MEK-ERK signaling cascade is known to be activated in several types of cancer, and regulates the transcription of proteins involved in apoptosis. In addition, studies have shown that mutations of the Raf component of the pathway can contribute to chemotherapy drug resistance. Ras as well as several kinases and phosphatases are responsible for regulating the Raf-MEK-ERK pathway. Often in cancers, Ras (a G-protein coupled receptor) is deregulated, allowing downstream signalling to proceed unchecked. Through several complex steps, Raf phosphorylates and activates MEK, which then phosphorylates and activates ERK. ERK is then able to exert its effects on several downstream targets. As such, therapies inhibiting upstream components of this pathway have become attractive targets for cancer treatment. Selumetinib exerts its effects by selectively inhibiting MEK1 and MEK2 which can effectively blunt the pleiotropic effects of the Ras-Raf-MEK-ERK cascade. By inhibiting this oncogenic pathway, selumetinib reduces cell proliferation, and promotes pro-apoptotic signal transduction.